bims-imicid 2023-04-09 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒04‒09
38 papers selected by
Dylan Ryan
University of Cambridge

Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.
Metabolic dysregulation impairs lymphocyte function during severe SARS-CoV-2 infection.
Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
Duodenal macrophages control dietary iron absorption via local degradation of transferrin.
Artesunate targets cellular metabolism to regulate the Th17/Treg cell balance.
The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts.
Transcriptional programing of T cell metabolism by STAT family transcription factors.
4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway.
The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome.
Macrophage function in adipose tissue homeostasis and metabolic inflammation.
Spleen fibroblastic reticular cell-derived acetylcholine promotes lipid metabolism to drive autoreactive B cell responses.
Mitochondria in Health, Disease, and Ageing.
The impact of microbiome dysbiosis on T cell function within the tumor microenvironment (TME).
Quorum-Sensing Signaling Molecule 2-Aminoacetophenone Mediates the Persistence of Pseudomonas aeruginosa in Macrophages by Interference with Autophagy through Epigenetic Regulation of Lipid Biosynthesis.
Metabolomic Profiling of Lungs from Mice Reveals the Variability of Metabolites in Pneumocystis Infection and the Metabolic Abnormalities in BAFF-R-Deficient Mice.
Role of microbiota short-chain fatty acid chains in the pathogenesis of autoimmune diseases.
WSSV exploits AMPK to activate mTORC2 signaling for proliferation by enhancing aerobic glycolysis.
Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue.
Metabolic shift underlies tumor progression and immune evasion in S-nitrosoglutathione reductase-deficient cancer.
A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma.
ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T-Cell Metabolism.
Single cell metabolic imaging of tumor and immune cells in vivo in melanoma bearing mice.
Gre factors help Salmonella adapt to oxidative stress by improving transcription elongation and fidelity of metabolic genes.
Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation.
SENP3 facilitates M1 macrophage polarization via the HIF-1α/PKM2 axis in lipopolysaccharide-induced acute lung injury.
A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.
Lysophosphatidylcholine facilitates the pathogenesis of psoriasis through activating keratinocytes and T cells differentiation via glycolysis.
Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury.
Lipid metabolism reprogramming in tumor-associated macrophages and implications for therapy.
MACROPHAGE-DERIVED OSTEOPONTIN (SPP1) PROTECTS FROM NON-ALCOHOLIC STEATOHEPATITIS.
The inhibition of glycolysis in T cells by a Jak inhibitor ameliorates the pathogenesis of allergic contact dermatitis in mice.
Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.
Host Lipid Transport Protein ORP1 Is Necessary for Coxiella burnetii Growth and Vacuole Expansion in Macrophages.
Amino Acid Starvation-Induced Glutamine Accumulation Enhances Pneumococcal Survival.
Potential use of the cholesterol transfer inhibitor U18666A as an antiviral drug for research on various viral infections.
Elevated exosome-transferrable lncRNA EPB41L4A-AS1 in CD56bright NK cells is responsible for the impaired NK function in neuroblastoma patients by suppressing cell glycolysis.
Oleanolic Acid Acetate Inhibits Mast Cell Activation in Ovalbumin-Induced Allergic Airway Inflammation.
Indole-3-pyruvic acid alleviates rheumatoid arthritis via the aryl hydrocarbon receptor pathway.

Cell. 2023 Apr 04. pii: S0092-8674(23)00271-4. [Epub ahead of print]

Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.

Mackenzie J Bender, Alex C McPherson, Catherine M Phelps, Surya P Pandey, Colin R Laughlin, Jake H Shapira, Luzmariel Medina Sanchez, Mohit Rana, Tanner G Richie, Tahliyah S Mims, Angela M Gocher-Demske, Luisa Cervantes-Barragan, Steven J Mullett, Stacy L Gelhaus, Tullia C Bruno, Nikki Cannon, John A McCulloch, Dario A A Vignali, Reinhard Hinterleitner, Alok V Joglekar, Joseph F Pierre, Sonny T M Lee, Diwakar Davar, Hassane M Zarour, Marlies Meisel.

  The use of probiotics by cancer patients is increasing, including among those undergoing immune checkpoint inhibitor (ICI) treatment. Here, we elucidate a critical microbial-host crosstalk between probiotic-released aryl hydrocarbon receptor (AhR) agonist indole-3-aldehyde (I3A) and CD8 T cells within the tumor microenvironment that potently enhances antitumor immunity and facilitates ICI in preclinical melanoma. Our study reveals that probiotic Lactobacillus reuteri (Lr) translocates to, colonizes, and persists within melanoma, where via its released dietary tryptophan catabolite I3A, it locally promotes interferon-γ-producing CD8 T cells, thereby bolstering ICI. Moreover, Lr-secreted I3A was both necessary and sufficient to drive antitumor immunity, and loss of AhR signaling within CD8 T cells abrogated Lr's antitumor effects. Further, a tryptophan-enriched diet potentiated both Lr- and ICI-induced antitumor immunity, dependent on CD8 T cell AhR signaling. Finally, we provide evidence for a potential role of I3A in promoting ICI efficacy and survival in advanced melanoma patients.

Keywords:  Lactobacillus reuteri; aryl hydrocarbon receptor; immune checkpoint inhibitor; indole-3-aldehyde; melanoma; microbial AhR ligands; microbial-host crosstalk; tryptophan; tumor microbiome

DOI:  https://doi.org/10.1016/j.cell.2023.03.011
Commun Biol. 2023 Apr 07. 6(1): 374

Metabolic dysregulation impairs lymphocyte function during severe SARS-CoV-2 infection.

Sanjeev Gurshaney, Anamaria Morales-Alvarez, Kevin Ezhakunnel, Andrew Manalo, Thien-Huong Huynh, Jun-Ichi Abe, Nhat-Tu Le, Daniela Weiskopf, Alessandro Sette, Daniel S Lupu, Stephen J Gardell, Hung Nguyen.

Cellular metabolic dysregulation is a consequence of SARS-CoV-2 infection that is a key determinant of disease severity. However, how metabolic perturbations influence immunological function during COVID-19 remains unclear. Here, using a combination of high-dimensional flow cytometry, cutting-edge single-cell metabolomics, and re-analysis of single-cell transcriptomic data, we demonstrate a global hypoxia-linked metabolic switch from fatty acid oxidation and mitochondrial respiration towards anaerobic, glucose-dependent metabolism in CD8+Tc, NKT, and epithelial cells. Consequently, we found that a strong dysregulation in immunometabolism was tied to increased cellular exhaustion, attenuated effector function, and impaired memory differentiation. Pharmacological inhibition of mitophagy with mdivi-1 reduced excess glucose metabolism, resulting in enhanced generation of SARS-CoV-2- specific CD8+Tc, increased cytokine secretion, and augmented memory cell proliferation. Taken together, our study provides critical insight regarding the cellular mechanisms underlying the effect of SARS-CoV-2 infection on host immune cell metabolism, and highlights immunometabolism as a promising therapeutic target for COVID-19 treatment.

DOI: https://doi.org/10.1038/s42003-023-04730-4
Nat Cell Biol. 2023 Apr 03.

Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.

Jordan A Berg, Youjia Zhou, Yeyun Ouyang, Ahmad A Cluntun, T Cameron Waller, Megan E Conway, Sara M Nowinski, Tyler Van Ry, Ian George, James E Cox, Bei Wang, Jared Rutter.

Metabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. Metabolism is a complex, interdependent network, and local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical and technical limitations have long created a bottleneck in metabolic data interpretation. To address these shortcomings, we developed Metaboverse, a user-friendly tool to facilitate data exploration and hypothesis generation. Here we introduce algorithms that leverage the metabolic network to extract complex reaction patterns from data. To minimize the impact of missing measurements within the network, we introduce methods that enable pattern recognition across multiple reactions. Using Metaboverse, we identify a previously undescribed metabolite signature that correlated with survival outcomes in early stage lung adenocarcinoma patients. Using a yeast model, we identify metabolic responses suggesting an adaptive role of citrate homeostasis during mitochondrial dysfunction facilitated by the citrate transporter, Ctp1. We demonstrate that Metaboverse augments the user's ability to extract meaningful patterns from multi-omics datasets to develop actionable hypotheses.

DOI: https://doi.org/10.1038/s41556-023-01117-9
Blood. 2023 Apr 05. pii: blood.2022016632. [Epub ahead of print]

Duodenal macrophages control dietary iron absorption via local degradation of transferrin.

Nyamdelger Sukhbaatar, Maria Schöller, Stephanie Deborah Fritsch, Monika Linke, Stefanie Horer, Manuela Träger, Mario Mazic, Stephan Forisch, Karine Gonzales, Jan Pascal Kahler, Carina Binder, Caroline Lassnig, Birgit Strobl, Mathias Mueller, Barbara Scheiber-Mojdehkar, Claudia Gundacker, Stefanie Dabsch, Renate Kain, Markus Hengstschläger, Steven Verhelst, Günter Weiss, Igor Theurl, Thomas Weichhart.

Iron is an essential cellular metal that is important for many physiological functions including erythropoiesis and host defense. It is absorbed from the diet in the duodenum and loaded onto transferrin, the main iron transport protein. Inefficient dietary iron uptake promotes many diseases, but mechanisms regulating iron absorption remain poorly understood. By assessing mice that harbor a macrophage-specific deletion of the tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, we found that these mice possessed various defects in iron metabolism including defective steady state erythropoiesis and a reduced saturation of transferrin with iron. This iron-deficiency phenotype was associated with an iron import block from the duodenal epithelial cells into the circulation. Activation of mTORC1 in villous duodenal CD68+ macrophages induced serine protease expression and promoted local degradation of transferrin, whereas depletion of macrophages in mice increased transferrin levels. Inhibition of mTORC1 with everolimus or serine protease activity with nafamostat restored transferrin levels in the Tsc2-deficient mice as well as transferrin saturation. Physiologically, transferrin levels were regulated in the duodenum during the prandial process and Citrobacter rodentium infection. These data suggest that duodenal macrophages determine iron transfer to the circulation by controlling transferrin availability in the lamina propria villi.

DOI: https://doi.org/10.1182/blood.2022016632
Inflamm Res. 2023 Apr 06.

Artesunate targets cellular metabolism to regulate the Th17/Treg cell balance.

Kun Chen, Liying Tang, Xiaolin Nong.

  INTRODUCTION: Metabolic reprogramming is one of the important mechanisms of cell differentiation, and different cells have different preferences for energy sources. During the differentiation of naive CD4 + T cells into Th17 and Treg cells, these cells show specific energy metabolism characteristics. Th17 cells depend on enhanced glycolysis, fatty acid synthesis, and glutaminolysis. In contrast, Treg cells are dependent on oxidative phosphorylation, fatty acid oxidation, and amino acid depletion. As a potent antimalarial drug, artesunate has been shown to modulate the Th17/Treg imbalance and regulate cell metabolism.METHODOLOGY: Relevant literatures on ART, cellular metabolism, glycolysis, lipid metabolism, amino acid metabolism, CD4 + T cells, Th17 cells, and Treg cells published from January 1, 2010 to now were searched in PubMed database.
CONCLUSION: In this review, we will highlight recent advances in which artesunate can restore the Th17/Treg imbalance in disease states by altering T-cell metabolism to influence differentiation and lineage selection. Data from the current study show that few studies have focused on the effect of ART on cellular metabolism. ART can affect the metabolic characteristics of T cells (glycolysis, lipid metabolism, and amino acid metabolism) and interfere with their differentiation lineage, thereby regulating the balance of Th17/Treg and alleviating the symptoms of the disease.

Keywords:  Amino acid metabolism; Artesunate; Cellular metabolism; Glycolysis; Lipid metabolism; Th17/Treg

DOI:  https://doi.org/10.1007/s00011-023-01729-9
Sci Adv. 2023 04 05. 9(14): eadg0731

The histone demethylase KDM5C controls female bone mass by promoting energy metabolism in osteoclasts.

Huadie Liu, Lukai Zhai, Ye Liu, Di Lu, Alexandra Vander Ark, Tao Yang, Connie M Krawczyk.

Women experience osteoporosis at higher rates than men. Aside from hormones, the mechanisms driving sex-dependent bone mass regulation are not well understood. Here, we demonstrate that the X-linked H3K4me2/3 demethylase KDM5C regulates sex-specific bone mass. Loss of KDM5C in hematopoietic stem cells or bone marrow monocytes increases bone mass in female but not male mice. Mechanistically, loss of KDM5C impairs the bioenergetic metabolism, resulting in impaired osteoclastogenesis. Treatment with the KDM5 inhibitor reduces osteoclastogenesis and energy metabolism of both female mice and human monocytes. Our report details a sex-dependent mechanism for bone homeostasis, connecting epigenetic regulation to osteoclast metabolism and positions KDM5C as a potential target for future treatment of osteoporosis in women.

DOI: https://doi.org/10.1126/sciadv.adg0731
Eur J Immunol. 2023 Apr 03. e2048825

Transcriptional programing of T cell metabolism by STAT family transcription factors.

Alejandro V Villarino.

  T cells adapt their metabolism to meet the energetic and biosynthetic demands imposed by changes in location, behavior and/or differentiation state. Many of these adaptations are controlled by cytokines. Traditionally, research on the metabolic properties of cytokines has focused on downstream signaling via the PI3K-AKT, mTOR, or ERK-MAPK pathways but recent studies indicate that JAK-STAT is also crucial. This review synthesizes current thinking on how JAK-STAT signaling influences T cell metabolism, focusing on adaptations necessary for the naïve, effector, regulatory, memory and resident-memory states. The overarching theme is that JAK-STAT has both direct and indirect effects. Direct regulation involves STATs localizing to and instructing expression of metabolism-related genes. Indirect regulation involves STATs instructing genes encoding upstream or regulatory factors, including cytokine receptors and other transcription factors, as well as non-canonical JAK-STAT activities. Cytokines impact a vast range of metabolic processes. Here, we focus on those that are most prominent in T cells; lipid, amino acid and nucleotide synthesis for anabolic metabolism, glycolysis, glutaminolysis, oxidative phosphorylation and fatty acid oxidation for catabolic metabolism. Ultimately, we advocate the idea that JAK-STAT is a key node in the complex network of signaling inputs and outputs which ensure that T cell metabolism meets lifestyle demands. This article is protected by copyright. All rights reserved.

Keywords:  Cytokine; JAK-STAT; Metabolism; T cell

DOI:  https://doi.org/10.1002/eji.202048825
Int Immunopharmacol. 2023 Mar 31. pii: S1567-5769(23)00425-3. [Epub ahead of print]118 110104

4-octyl itaconate ameliorates alveolar macrophage pyroptosis against ARDS via rescuing mitochondrial dysfunction and suppressing the cGAS/STING pathway.

Yu-Tong Wu, Wen-Ting Xu, Li Zheng, Sheng Wang, Juan Wei, Mei-Yun Liu, Huan-Ping Zhou, Quan-Fu Li, Xuan Shi, Xin Lv.

  Acute respiratory distress syndrome (ARDS) is a high-mortality pulmonary disorder characterized by an intense inflammatory response and a cytokine storm. As of yet, there is no proven effective therapy for ARDS. Itaconate, an immunomodulatory derivative accumulated during inflammatory macrophage activation, has attracted widespread attention for its potent anti-inflammatory and anti-oxidative properties. This study pointed to explore the protective impacts of 4-octyl itaconate (4-OI) on ARDS. The results showed that lung injury was attenuated markedly after 4-OI pre-treatment, as represented by decreased pulmonary edema, inflammatory cell infiltration, and production of inflammatory factors. LPS stimulation induced NLRP3-mediated pyroptosis in vitro and in vivo, as represented by the cleavage of gasdermin D (GSDMD), IL-18 and IL-1β release, and these changes could be prevented by 4-OI pretreatment. Mechanistically, 4-OI eliminated mitochondrial reactive oxygen species (mtROS) and mtDNA escaping to the cytosol through the opening mitochondrial permeability transition pore (mPTP) in alveolar macrophages (AMs) under oxidative stress. In addition, 4-OI pretreatment markedly downregulated cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) expression, and interferon regulatory factor 3 (IRF3) phosphorylation in vitro and in vivo. Meanwhile, inhibition of STING/IRF3 pathway alleviated NLRP3-mediated pyroptosis induced by LPS in vitro. Taken together, this study indicated that 4-OI ameliorated ARDS by rescuing mitochondrial dysfunction and inhibiting NLRP3-mediated macrophage pyroptosis in a STING/IRF3-dependent manner, which further revealed the potential mechanism of itaconate in preventing inflammatory diseases.

Keywords:  4-octyl itaconate; Acute respiratory distress syndrome; Macrophage pyroptosis; Mitochondrial dysfunction; NLRP3 inflammasome; cGAS/STING pathway

DOI:  https://doi.org/10.1016/j.intimp.2023.110104
Front Immunol. 2023 ;14 1117548

The role of immunometabolism in macrophage polarization and its impact on acute lung injury/acute respiratory distress syndrome.

Lian Wang, Dongguang Wang, Tianli Zhang, Yao Ma, Xiang Tong, Hong Fan.

  Lung macrophages constitute the first line of defense against airborne particles and microbes and are key to maintaining pulmonary immune homeostasis. There is increasing evidence suggesting that macrophages also participate in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), including the modulation of inflammatory responses and the repair of damaged lung tissues. The diversity of their functions may be attributed to their polarized states. Classically activated or inflammatory (M1) macrophages and alternatively activated or anti-inflammatory (M2) macrophages are the two main polarized macrophage phenotypes. The precise regulatory mechanism of macrophage polarization is a complex process that is not completely understood. A growing body of literature on immunometabolism has demonstrated the essential role of immunometabolism and its metabolic intermediates in macrophage polarization. In this review, we summarize macrophage polarization phenotypes, the role of immunometabolism, and its metabolic intermediates in macrophage polarization and ALI/ARDS, which may represent a new target and therapeutic direction.

Keywords:  acute lung injury; acute respiratory distress syndrome; immunometabolism; macrophage polarization; metabolic reprogramming; polarization regulation

DOI:  https://doi.org/10.3389/fimmu.2023.1117548
Nat Immunol. 2023 Apr 03.

Macrophage function in adipose tissue homeostasis and metabolic inflammation.

Triantafyllos Chavakis, Vasileia Ismini Alexaki, Anthony W Ferrante.

Obesity-related metabolic organ inflammation contributes to cardiometabolic disorders. In obese individuals, changes in lipid fluxes and storage elicit immune responses in the adipose tissue (AT), including expansion of immune cell populations and qualitative changes in the function of these cells. Although traditional models of metabolic inflammation posit that these immune responses disturb metabolic organ function, studies now suggest that immune cells, especially AT macrophages (ATMs), also have important adaptive functions in lipid homeostasis in states in which the metabolic function of adipocytes is taxed. Adverse consequences of AT metabolic inflammation might result from failure to maintain local lipid homeostasis and long-term effects on immune cells beyond the AT. Here we review the complex function of ATMs in AT homeostasis and metabolic inflammation. Additionally, we hypothesize that trained immunity, which involves long-term functional adaptations of myeloid cells and their bone marrow progenitors, can provide a model by which metabolic perturbations trigger chronic systemic inflammation.

DOI: https://doi.org/10.1038/s41590-023-01479-0
Cell Metab. 2023 Mar 29. pii: S1550-4131(23)00088-8. [Epub ahead of print]

Spleen fibroblastic reticular cell-derived acetylcholine promotes lipid metabolism to drive autoreactive B cell responses.

Qin Zeng, Shuyi Wang, Mengyuan Li, Shuang Wang, Chaohuan Guo, Xinyuan Ruan, Ryu Watanabe, Yimei Lai, Yuefang Huang, Xiaoyu Yin, Chuanzhao Zhang, Binfeng Chen, Niansheng Yang, Hui Zhang.

  Autoreactive B cell responses are essential for the development of systemic lupus erythematosus (SLE). Fibroblastic reticular cells (FRCs) are known to construct lymphoid compartments and regulate immune functions. Here, we identify spleen FRC-derived acetylcholine (ACh) as a key factor that controls autoreactive B cell responses in SLE. In SLE, CD36-mediated lipid uptake leads to enhanced mitochondrial oxidative phosphorylation in B cells. Accordingly, the inhibition of fatty acid oxidation results in reduced autoreactive B cell responses and ameliorated diseases in lupus mice. Ablation of CD36 in B cells impairs lipid uptake and differentiation of autoreactive B cells during autoimmune induction. Mechanistically, spleen FRC-derived ACh promotes lipid influx and generation of autoreactive B cells through CD36. Together, our data uncover a novel function of spleen FRCs in lipid metabolism and B cell differentiation, placing spleen FRC-derived ACh in a key position in promoting autoreactive B cells in SLE.

Keywords:  CD36; acetylcholine; autoreactive B cell responses; choline acetyltransferase; fibroblastic reticular cells; lipid metabolism; mitochondrial respiration; spleen; systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.cmet.2023.03.010
Physiol Rev. 2023 Apr 06.

Mitochondria in Health, Disease, and Ageing.

John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.

  Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.

Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy

DOI:  https://doi.org/10.1152/physrev.00058.2021
Front Cell Dev Biol. 2023 ;11 1141215

The impact of microbiome dysbiosis on T cell function within the tumor microenvironment (TME).

Michelle P DiPalma, Joseph N Blattman.

  Insights into the effect of the microbiome's composition on immune cell function have recently been discerned and further characterized. Microbiome dysbiosis can result in functional alterations across immune cells, including those required for innate and adaptive immune responses to malignancies and immunotherapy treatment. Dysbiosis can yield changes in or elimination of metabolite secretions, such as short-chain fatty acids (SCFAs), from certain bacterial species that are believed to impact proper immune cell function. Such alterations within the tumor microenvironment (TME) can significantly affect T cell function and survival necessary for eliminating cancerous cells. Understanding these effects is essential to improve the immune system's ability to fight malignancies and the subsequent efficacy of immunotherapies that rely on T cells. In this review, we assess typical T cell response to malignancies, classify the known impact of the microbiome and particular metabolites on T cells, discuss how dysbiosis can affect their function in the TME then further describe the impact of the microbiome on T cell-based immunotherapy treatment, with an emphasis on recent developments in the field. Understanding the impact of dysbiosis on T cell function within the TME can carry substantial implications for the design of immunotherapy treatments and further our understanding of factors that could impact how the immune system combats malignancies.

Keywords:  T cell; T cell signaling; dysbiosis; immunotherapy; metabolites; microbiome; short chain fatty acids (SCFAs); tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fcell.2023.1141215
mBio. 2023 Apr 03. e0015923

Quorum-Sensing Signaling Molecule 2-Aminoacetophenone Mediates the Persistence of Pseudomonas aeruginosa in Macrophages by Interference with Autophagy through Epigenetic Regulation of Lipid Biosynthesis.

Arijit Chakraborty, Asel Kabashi, Samuel Wilk, Laurence G Rahme.

  Macrophages are crucial components of the host's defense against pathogens. Recent studies indicate that macrophage functions are influenced by lipid metabolism. However, knowledge of how bacterial pathogens exploit macrophage lipid metabolism for their benefit remains rudimentary. We have shown that the Pseudomonas aeruginosa MvfR-regulated quorum-sensing (QS) signaling molecule 2-aminoacetophenone (2-AA) mediates epigenetic and metabolic changes associated with this pathogen's persistence in vivo. We provide evidence that 2-AA counteracts the ability of macrophages to clear the intracellular P. aeruginosa, leading to persistence. The intracellular action of 2-AA in macrophages is linked to reduced autophagic functions and the impaired expression of a central lipogenic gene, stearoyl-CoA desaturase 1 (Scd1), which catalyzes the biosynthesis of monounsaturated fatty acids. 2-AA also reduces the expression of the autophagic genes Unc-51-like autophagy activating kinase 1 (ULK1) and Beclin1 and the levels of the autophagosomal membrane protein microtubule-associated protein 1, light chain 3 isoform B (LC3B) and p62. Reduced autophagy is accompanied by the reduced expression of the lipogenic gene Scd1, preventing bacterial clearance. Adding the SCD1 substrates palmitoyl-CoA and stearoyl-CoA increases P. aeruginosa clearance by macrophages. The impact of 2-AA on lipogenic gene expression and autophagic machinery is histone deacetylase 1 (HDAC1) mediated, implicating the HDAC1 epigenetic marks at the promoter sites of Scd1 and Beclin1 genes. This work provides novel insights into the complex metabolic alterations and epigenetic regulation promoted by QS and uncovers additional 2-AA actions supporting P. aeruginosa sustainment in macrophages. These findings may aid in designing host-directed therapeutics and protective interventions against P. aeruginosa persistence. IMPORTANCE This work sheds new light on how P. aeruginosa limits bacterial clearance in macrophages through 2-aminoacetophenone (2-AA), a secreted signaling molecule by this pathogen that is regulated by the quorum-sensing transcription factor MvfR. The action of 2-AA on the lipid biosynthesis gene Scd1 and the autophagic genes ULK1 and Beclin1 appears to secure the reduced intracellular clearance of P. aeruginosa by macrophages. In support of the 2-AA effect on lipid biosynthesis, the ability of macrophages to reduce the intracellular P. aeruginosa burden is reinstated following the supplementation of palmitoyl-CoA and stearoyl-CoA. The 2-AA-mediated reduction of Scd1 and Beclin1 expression is linked to chromatin modifications, implicating the enzyme histone deacetylase 1 (HDAC1), thus opening new avenues for future strategies against this pathogen's persistence. Overall, the knowledge obtained from this work provides for developing new therapeutics against P. aeruginosa.

Keywords:  2-aminoacetophenone; MvfR; PqsR; Pseudomonas aeruginosa; Scd1; autophagy; epigenetic reprogramming; fatty acids; histone deacetylation; immunometabolism; macrophages; persistence; quorum sensing

DOI:  https://doi.org/10.1128/mbio.00159-23
J Inflamm Res. 2023 ;16 1357-1373

Metabolomic Profiling of Lungs from Mice Reveals the Variability of Metabolites in Pneumocystis Infection and the Metabolic Abnormalities in BAFF-R-Deficient Mice.

Heng-Mo Rong, Han-Yu-Jie Kang, Zhao-Hui Tong.

  Purpose: The incidence of Pneumocystis pneumonia (PCP) in patients without human immunodeficiency virus (HIV) has been increasing. In this study, we aimed to investigate the metabolic changes in Pneumocystis infection and the metabolic abnormalities in B-cell-activating factor receptor (BAFF-R)-deficient mice with Pneumocystis infection.Methods: The important function of B cells during Pneumocystis infection is increasingly recognized. In this study, a Pneumocystis-infected mouse model was constructed in BAFF-R-/- mice and wild-type (WT) mice. Lungs of uninfected WT C57BL/6, WT Pneumocystis-infected, and BAFF-R-/- Pneumocystis-infected mice were used for metabolomic analyses to compare the metabolomic profiles among the groups, with the aim of exploring the metabolic influence of Pneumocystis infection and the influence of mature B-cell deficiency during infection.
Results: The results indicated that many metabolites, mainly lipids and lipid-like molecules, were dysregulated in Pneumocystis-infected WT mice compared with uninfected WT C57BL/6 mice. The data also demonstrated significant changes in tryptophan metabolism, and the expression levels of key enzymes of tryptophan metabolism, such as indoleamine 2,3-dioxygenase 1 (IDO1), were significantly upregulated. In addition, B-cell development and function might be associated with lipid metabolism. We found a lower level of alitretinoin and the abnormalities of fatty acid metabolism in BAFF-R-/- Pneumocystis-infected mice. The mRNA levels of enzymes associated with fatty acid metabolism in the lung were upregulated in BAFF-R-/- Pneumocystis-infected mice and positively correlated with the level of IL17A, thus suggesting that the abnormalities of fatty acid metabolism may be associated with greater inflammatory cell infiltration in the lung tissue of BAFF-R-/- Pneumocystis-infected mice compared with the WT Pneumocystis-infected mice.
Conclusion: Our data revealed the variability of metabolites in Pneumocystis-infected mice, suggesting that the metabolism plays a vital role in the immune response to Pneumocystis infection.

Keywords:  B lymphocytes; Pneumocystis pneumonia; inflammation; metabolomics

DOI:  https://doi.org/10.2147/JIR.S394608
Biomed Pharmacother. 2023 Mar 31. pii: S0753-3322(23)00408-0. [Epub ahead of print]162 114620

Role of microbiota short-chain fatty acid chains in the pathogenesis of autoimmune diseases.

Ashkan Rasouli-Saravani, Kasra Jahankhani, Shadi Moradi, Melika Gorgani, Zahra Shafaghat, Zahra Mirsanei, Amirreza Mehmandar, Rasoul Mirzaei.

  There is emerging evidence that microbiota and its metabolites play an important role in helath and diseases. In this regard, gut microbiota has been found as a crucial component that influences immune responses as well as immune-related disorders such as autoimmune diseases. Gut bacterial dysbiosis has been shown to cause disease and altered microbiota metabolite synthesis, leading to immunological and metabolic dysregulation. Of note, microbiota in the gut produce short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, and remodeling in these microbiota metabolites has been linked to the pathophysiology of a number of autoimmune disorders such as type 1 diabetes, multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, celiac disease, and systemic lupus erythematosus. In this review, we will address the most recent findings from the most noteworthy studies investigating the impact of microbiota SCFAs on various autoimmune diseases.

Keywords:  GPCRs; HDAC; Microbiota; SCFAs, Autoimmune diseases

DOI:  https://doi.org/10.1016/j.biopha.2023.114620
Commun Biol. 2023 04 03. 6(1): 361

WSSV exploits AMPK to activate mTORC2 signaling for proliferation by enhancing aerobic glycolysis.

Peng Zhang, Hai-Jing Fu, Li-Xia Lv, Chen-Fei Liu, Chang Han, Xiao-Fan Zhao, Jin-Xing Wang.

AMPK plays significant roles in the modulation of metabolic reprogramming and viral infection. However, the detailed mechanism by which AMPK affects viral infection is unclear. The present study aims to determine how AMPK influences white spot syndrome virus (WSSV) infection in shrimp (Marsupenaeus japonicus). Here, we find that AMPK expression and phosphorylation are significantly upregulated in WSSV-infected shrimp. WSSV replication decreases remarkably after knockdown of Ampkα and the shrimp survival rate of AMPK-inhibitor injection shrimp increases significantly, suggesting that AMPK is beneficial for WSSV proliferation. Mechanistically, WSSV infection increases intracellular Ca2+ level, and activates CaMKK, which result in AMPK phosphorylation and partial nuclear translocation. AMPK directly activates mTORC2-AKT signaling pathway to phosphorylate key enzymes of glycolysis in the cytosol and promotes expression of Hif1α to mediate transcription of key glycolytic enzyme genes, both of which lead to increased glycolysis to provide energy for WSSV proliferation. Our findings reveal a novel mechanism by which WSSV exploits the host CaMKK-AMPK-mTORC2 pathway for its proliferation, and suggest that AMPK might be a target for WSSV control in shrimp aquaculture.

DOI: https://doi.org/10.1038/s42003-023-04735-z
Front Immunol. 2023 ;14 1014778

Molecular tracking of insulin resistance and inflammation development on visceral adipose tissue.

Antonio Bensussen, José Antonio Torres-Magallanes, Elena Roces de Álvarez-Buylla.

  Background: Visceral adipose tissue (VAT) is one of the most important sources of proinflammatory molecules in obese people and it conditions the appearance of insulin resistance and diabetes. Thus, understanding the synergies between adipocytes and VAT-resident immune cells is essential for the treatment of insulin resistance and diabetes.Methods: We collected information available on databases and specialized literature to construct regulatory networks of VAT resident cells, such as adipocytes, CD4+ T lymphocytes and macrophages. These networks were used to build stochastic models based on Markov chains to visualize phenotypic changes on VAT resident cells under several physiological contexts, including obesity and diabetes mellitus.
Results: Stochastic models showed that in lean people, insulin produces inflammation in adipocytes as a homeostatic mechanism to downregulate glucose intake. However, when the VAT tolerance to inflammation is exceeded, adipocytes lose insulin sensitivity according to severity of the inflammatory condition. Molecularly, insulin resistance is initiated by inflammatory pathways and sustained by intracellular ceramide signaling. Furthermore, our data show that insulin resistance potentiates the effector response of immune cells, which suggests its role in the mechanism of nutrient redirection. Finally, our models show that insulin resistance cannot be inhibited by anti-inflammatory therapies alone.
Conclusion: Insulin resistance controls adipocyte glucose intake under homeostatic conditions. However, metabolic alterations such as obesity, enhances insulin resistance in adipocytes, redirecting nutrients to immune cells, permanently sustaining local inflammation in the VAT.

Keywords:  CD4+ T cells; adipocytes; diabetes mellitus; insulin resistance; macrophages; stochastic dynamic network models; visceral adipose tissue

DOI:  https://doi.org/10.3389/fimmu.2023.1014778
J Pathol. 2023 Apr 05.

Metabolic shift underlies tumor progression and immune evasion in S-nitrosoglutathione reductase-deficient cancer.

Rafael Mena-Osuna, Ana Mantrana, Silvia Guil-Luna, María Teresa Sánchez-Montero, Carmen Navarrete-Sirvent, Teresa Morales-Ruiz, Aurora Rivas-Crespo, Marta Toledano-Fonseca, María Victoria García-Ortíz, Gema García-Jurado, María Auxiliadora Gómez-España, Rafael González-Fernández, Carlos Villar, Francisco Javier Medina-Fernández, José Manuel Villalba, Enrique Aranda, Antonio Rodríguez-Ariza.

  S-nitrosoglutathione reductase (GSNOR) is a denitrosylase enzyme that has been suggested to play a tumor suppressor role, although the mechanisms responsible are still largely unclear. In this study, we show that GSNOR deficiency in tumors is associated with poor prognostic histopathological features and poor survival in patients with colorectal cancer (CRC). GSNOR-low tumors were characterized by an immunosuppressive microenvironment with exclusion of cytotoxic CD8+ T cells. Notably, GSNOR-low tumors exhibited an immune evasive proteomic signature along with an altered energy metabolism characterized by impaired oxidative phosphorylation (OXPHOS) and energetic dependence on glycolytic activity. CRISPR-Cas9-mediated generation of GSNOR gene knockout (KO) CRC cells confirmed in vitro and in vivo that GSNOR-deficiency conferred higher tumorigenic and tumor-initiating capacities. Moreover, GSNOR-KO cells possessed enhanced immune evasive properties and resistance to immunotherapy, as revealed following xenografting them into humanized mouse models. Importantly, GSNOR-KO cells were characterized by a metabolic shift from OXPHOS to glycolysis to produce energy, as indicated by increased lactate secretion, higher sensitivity to 2-deoxyglucose (2DG), and a fragmented mitochondrial network. Real-time metabolic analysis revealed that GSNOR-KO cells operated close to their maximal glycolytic rate, as a compensation for lower OXPHOS levels, explaining their higher sensitivity to 2DG. Remarkably, this higher susceptibility to glycolysis inhibition with 2DG was validated in patient-derived xenografts and organoids from clinical GSNOR-low tumors. In conclusion, our data support the idea that metabolic reprogramming induced by GSNOR deficiency is an important mechanism for tumor progression and immune evasion in CRC and that the metabolic vulnerabilities associated with the deficiency of this denitrosylase can be exploited therapeutically. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  GSNOR; colorectal cancer; glycolysis; immune evasion; immunotherapy; metabolism; mitochondria; nitric oxide; oxidative phosphorylation

DOI:  https://doi.org/10.1002/path.6080
Front Immunol. 2023 ;14 1095195

A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma.

Renate Pichler, Peter J Siska, Piotr Tymoszuk, Agnieszka Martowicz, Gerold Untergasser, Roman Mayr, Florian Weber, Andreas Seeber, Florian Kocher, Dominik A Barth, Martin Pichler, Martin Thurnher.

  Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.

Keywords:  IDO, biomarker; OXPHOS; RCC; T cells; chemokines; immunotherapy; metabolism

DOI:  https://doi.org/10.3389/fimmu.2023.1095195
Adv Sci (Weinh). 2023 Apr 04. e2206768

ERK Inhibition Promotes Engraftment of Allografts by Reprogramming T-Cell Metabolism.

Xiaosheng Tan, Changxing Qi, Xiangli Zhao, Lingjuan Sun, Mi Wu, Weiguang Sun, Lianghu Gu, Fengqing Wang, Hao Feng, Xia Huang, Bin Xie, Zhengyi Shi, Peiling Xie, Meng Wu, Yonghui Zhang, Gang Chen.

  Extracellular regulated protein kinases (ERK) signaling is a master regulator of cell behavior, life, and fate. Although ERK pathway is shown to be involved in T-cell activation, little is known about its role in the development of allograft rejection. Here, it is reported that ERK signaling pathway is activated in allograft-infiltrating T cells. On the basis of surface plasmon resonance technology, lycorine is identified as an ERK-specific inhibitor. ERK inhibition by lycorine significantly prolongs allograft survival in a stringent mouse cardiac allotransplant model. As compared to untreated mice, lycorine-treated mice show a decrease in the number and activation of allograft-infiltrated T cells. It is further confirmed that lycorine-treated mouse and human T cells are less responsive to stimulation in vitro, as indicated by their low proliferative rates and decreased cytokine production. Mechanistic studies reveal that T cells treated with lycorine exhibit mitochondrial dysfunction, resulting in metabolic reprogramming upon stimulation. Transcriptome analysis of lycorine-treated T cells reveals an enrichment in a series of downregulated terms related to immune response, the mitogen-activated protein kinase cascade, and metabolic processes. These findings offer new insights into the development of immunosuppressive agents by targeting the ERK pathway involved in T-cell activation and allograft rejection.

Keywords:  allograft rejection; extracellular regulated protein kinases (ERK); lycorine; metabolism; mitochondria

DOI:  https://doi.org/10.1002/advs.202206768
Front Oncol. 2023 ;13 1110503

Single cell metabolic imaging of tumor and immune cells in vivo in melanoma bearing mice.

Alexa R Heaton, Peter R Rehani, Anna Hoefges, Angelica F Lopez, Amy K Erbe, Paul M Sondel, Melissa C Skala.

  Introduction: Metabolic reprogramming of cancer and immune cells occurs during tumorigenesis and has a significant impact on cancer progression. Unfortunately, current techniques to measure tumor and immune cell metabolism require sample destruction and/or cell isolations that remove the spatial context. Two-photon fluorescence lifetime imaging microscopy (FLIM) of the autofluorescent metabolic coenzymes nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavin adenine dinucleotide (FAD) provides in vivo images of cell metabolism at a single cell level.Methods: Here, we report an immunocompetent mCherry reporter mouse model for immune cells that express CD4 either during differentiation or CD4 and/or CD8 in their mature state and perform in vivo imaging of immune and cancer cells within a syngeneic B78 melanoma model. We also report an algorithm for single cell segmentation of mCherry-expressing immune cells within in vivo images.
Results: We found that immune cells within B78 tumors exhibited decreased FAD mean lifetime and an increased proportion of bound FAD compared to immune cells within spleens. Tumor infiltrating immune cell size also increased compared to immune cells from spleens. These changes are consistent with a shift towards increased activation and proliferation in tumor infiltrating immune cells compared to immune cells from spleens. Tumor infiltrating immune cells exhibited increased FAD mean lifetime and increased protein-bound FAD lifetime compared to B78 tumor cells within the same tumor. Single cell metabolic heterogeneity was observed in both immune and tumor cells in vivo.
Discussion: This approach can be used to monitor single cell metabolic heterogeneity in tumor cells and immune cells to study promising treatments for cancer in the native in vivo context.

Keywords:  autofluorescence; immune cells; intravital imaging; melanoma; metabolism; multiphoton/two-photon imaging; murine models

DOI:  https://doi.org/10.3389/fonc.2023.1110503
PLoS Biol. 2023 Apr;21(4): e3002051

Gre factors help Salmonella adapt to oxidative stress by improving transcription elongation and fidelity of metabolic genes.

Sashi Kant, James Karl A Till, Lin Liu, Alyssa Margolis, Siva Uppalapati, Ju-Sim Kim, Andres Vazquez-Torres.

Detoxification, scavenging, and repair systems embody the archetypical antioxidant defenses of prokaryotic and eukaryotic cells. Metabolic rewiring also aids with the adaptation of bacteria to oxidative stress. Evolutionarily diverse bacteria combat the toxicity of reactive oxygen species (ROS) by actively engaging the stringent response, a stress program that controls many metabolic pathways at the level of transcription initiation via guanosine tetraphosphate and the α-helical DksA protein. Studies herein with Salmonella demonstrate that the interactions of structurally related, but functionally unique, α-helical Gre factors with the secondary channel of RNA polymerase elicit the expression of metabolic signatures that are associated with resistance to oxidative killing. Gre proteins both improve transcriptional fidelity of metabolic genes and resolve pauses in ternary elongation complexes of Embden-Meyerhof-Parnas (EMP) glycolysis and aerobic respiration genes. The Gre-directed utilization of glucose in overflow and aerobic metabolism satisfies the energetic and redox demands of Salmonella, while preventing the occurrence of amino acid bradytrophies. The resolution of transcriptional pauses in EMP glycolysis and aerobic respiration genes by Gre factors safeguards Salmonella from the cytotoxicity of phagocyte NADPH oxidase in the innate host response. In particular, the activation of cytochrome bd protects Salmonella from phagocyte NADPH oxidase-dependent killing by promoting glucose utilization, redox balancing, and energy production. Control of transcription fidelity and elongation by Gre factors represent important points in the regulation of metabolic programs supporting bacterial pathogenesis.

DOI: https://doi.org/10.1371/journal.pbio.3002051
Genes Dis. 2023 Jan;10(1): 7-9

Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation.

Nian Jiang, Bowen Xie, Ming Fan, Jian Jian Li.

  Although extensively studied, it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy. Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors. However, accumulating evidence indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating mitochondrial OXPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation. Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis. Interestingly, data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.

Keywords:  CD47; Immune checkpoint; Immunotherapy; Metabolic rewiring; Radiation therapy; Tumor acquired resistance

DOI:  https://doi.org/10.1016/j.gendis.2022.07.019
Innate Immun. 2023 Apr 05. 17534259231166212

SENP3 facilitates M1 macrophage polarization via the HIF-1α/PKM2 axis in lipopolysaccharide-induced acute lung injury.

Shuangjun He, Chenyu Fan, Yiming Ji, Qian Su, Feng Zhao, Cuiying Xie, Xuelian Chen, Yang Zhang, Yi Chen.

  M1/M2 macrophage polarization plays a pivotal role in the development of acute lung injury (ALI). The hypoxia-inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis, which functions upstream of macrophage polarization, has been implicated in this process. The function of HIF-1α is known to be tightly regulated by SUMOylation. Upregulation of SUMO-specific peptidase 3 (SENP3), a deSUMOylation enzyme, is induced by reactive oxygen species (ROS), which are abundantly produced during ALI. To explore the links between SENP3, macrophage polarization, and lung injury, we used mice with Senp3 conditional knockout in myeloid cells. In the lipopolysaccharide (LPS)-induced ALI model, we found that in vitro and in vivo SENP3 deficiency markedly inhibited M1 polarization and production of pro-inflammatory cytokines and alleviated lung injury. Further, we demonstrated that SENP3 deficiency suppressed the LPS-induced inflammatory response through PKM2 in a HIF-1α-dependent manner. Moreover, mice injected with LPS after PKM2 inhibitor (shikonin) treatment displayed inhibition of M1 macrophage polarization and reduced lung injury. In summary, this work revealed that SENP3 promotes M1 macrophage polarization and production of proinflammatory cytokines via the HIF-1α/PKM2 axis, contributing to lung injury; thus, SENP3 may represent a potential therapeutic target for ALI treatment.

Keywords:  HIF-1α; Macrophage; PKM2; SENP3; SUMOylation; acute lung injury

DOI:  https://doi.org/10.1177/17534259231166212
PLoS Pathog. 2023 Apr 07. 19(4): e1010942

A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

Mylene Vaillancourt, Anna Clara Milesi Galdino, Sam P Limsuwannarot, Diana Celedonio, Elizabeth Dimitrova, Matthew Broerman, Catherine Bresee, Yohei Doi, Janet S Lee, William C Parks, Peter Jorth.

During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased pyoverdine and pyochelin siderophore gene expression, causing macrophage ferroptosis and lysis. We show that iron-bound pyochelin was sufficient to cause macrophage ferroptosis and lysis, however, apo-pyochelin, iron-bound pyoverdine, or apo-pyoverdine were insufficient to kill macrophages. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.

DOI: https://doi.org/10.1371/journal.ppat.1010942
J Eur Acad Dermatol Venereol. 2023 Apr 04.

Lysophosphatidylcholine facilitates the pathogenesis of psoriasis through activating keratinocytes and T cells differentiation via glycolysis.

Panpan Liu, Youyou Zhou, Chao Chen, Bei Yan, Lei Li, Wu Zhu, Jie Li, MingLiang Chen, Juan Su, Yehong Kuang, Xiang Chen, Cong Peng.

BACKGROUND: Although abnormal metabolism plays a critical role in the pathogenesis of psoriasis, the details are unclear.OBJECTIVES: Here, we identified to explore the role and mechanism of lysophosphatidylcholine (LPC) on the pathogenesis of psoriasis.
METHODS: The level of LPC in plasma and skin lesions and the expression of G2A on skin lesions of psoriasis patients were detected by enzyme-linked immunosorbent assay, liquid chromatography-tandem mass spectrometry, or immunohistochemistry, respectively. The glycolysis in the skin lesions of imiquimod (IMQ)-induced psoriasis-like mouse model was detected by extracellular acidification rate. LPC was subcutaneously injected into IMQ-treated mouse ears, and the phenotype as well as the glycolysis were evaluated. Exploring the effects and mechanism of LPC on keratinocytes and CD4+ T cells by culturing primary keratinocytes and CD4+ T in vitro.
RESULTS: We found that LPC was significantly increased both in the plasma and skin lesions of psoriatic patients, while G2A, exerting an essential role in LPC inducing biological functions, was increased in psoriatic lesions. The abundance of LPC was positively correlated with glycolytic activity in the psoriasis-like mouse model. LPC treatment facilitated psoriasis-like inflammation and glycolytic activity in skin lesions. Mechanistically, the LPC/G2A axis significantly triggered glycolytic activity and produced inflammatory factors in keratinocytes, and blockade of glycolysis abrogated LPC-induced expression of inflammatory mediators in keratinocytes. LPC activated STAT1, resulting in recognition and binding to the promoters of GCK and PKLR, which are glycolytic rate-limiting enzymes. Furthermore, the LPC/G2A axis directly benefited Th1 differentiation, which was dependent on LPC-induced glycolytic activity. Notably, LPC indirectly facilitated Th17 differentiation by inducing the secretion of IL-1β in keratinocytes-T cells coculture system.
CONCLUSIONS: Taken together, our findings revealed the role of the LPC/G2A axis in the pathogenesis of psoriasis; targeting LPC/G2A is a potential strategy for psoriasis therapy.

DOI: https://doi.org/10.1111/jdv.19088
Front Immunol. 2023 ;14 1131146

Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury.

Kenji Morino, Kazufumi Kunimura, Yuki Sugiura, Yoshihiro Izumi, Keisuke Matsubara, Sayaka Akiyoshi, Rae Maeda, Kenichiro Hirotani, Daiji Sakata, Seiya Mizuno, Satoru Takahashi, Takeshi Bamba, Takehito Uruno, Yoshinori Fukui.

  During mucosal injury, intestinal immune cells play a crucial role in eliminating invading bacteria. However, as the excessive accumulation of immune cells promotes inflammation and delays tissue repair, it is essential to identify the mechanism that limits the infiltration of immune cells to the mucosal-luminal interface. Cholesterol sulfate (CS) is the lipid product of the sulfotransferase SULT2B1 and suppresses immune reactions by inhibiting DOCK2-mediated Rac activation. In this study, we aimed to elucidate the physiological role of CS in the intestinal tract. We found that, in the small intestine and colon, CS is predominantly produced in the epithelial cells close to the lumen. While dextran sodium sulfate (DSS)-induced colitis was exacerbated in Sult2b1-deficient mice with increased prevalence of neutrophils, the elimination of either neutrophils or intestinal bacteria in Sult2b1-deficient mice attenuated disease development. Similar results were obtained when the Dock2 was genetically deleted in Sult2b1-deficient mice. In addition, we also show that indomethacin-induced ulcer formation in the small intestine was exacerbated in Sult2b1-deficient mice and was ameliorated by CS administration. Thus, our results uncover that CS acts on inflammatory neutrophils, and prevents excessive gut inflammation by inhibiting the Rac activator DOCK2. The administration of CS may be a novel therapeutic strategy for inflammatory bowel disease and non-steroidal anti-inflammatory drug-induced ulcers.

Keywords:  CyTOF; DOCK2; SULT2B1; cholesterol sulfate; gut inflammation; mass spectrometry; neutrophil

DOI:  https://doi.org/10.3389/fimmu.2023.1131146
Lipids Health Dis. 2023 Mar 31. 22(1): 45

Lipid metabolism reprogramming in tumor-associated macrophages and implications for therapy.

Xuehan Qiao, Zhangmin Hu, Fen Xiong, Yufei Yang, Chen Peng, Deqiang Wang, Xiaoqin Li.

  The tumormicroenvironment (TME) plays a key role in tumor progression. Tumor-associated macrophages (TAMs), which are natural immune cells abundantin the TME, are mainly divided into the anti-tumor M1 subtype and pro-tumor M2 subtype. Due to the high plasticity of TAMs, the conversion of the M1 to M2 phenotype in hypoxic and hypoglycemic TME promotes cancer progression, which is closely related to lipid metabolism. Key factors of lipid metabolism in TAMs, including peroxisome proliferator-activated receptor and lipoxygenase, promote the formation of a tumor immunosuppressive microenvironment and facilitate immune escape. In addition, tumor cells promote lipid accumulation in TAMs, causing TAMs to polarize to the M2 phenotype. Moreover, other factors of lipid metabolism, such as abhydrolase domain containing 5 and fatty acid binding protein, have both promoting and inhibiting effects on tumor cells. Therefore, further research on lipid metabolism in tumors is still required. In addition, statins, as core drugs regulating cholesterol metabolism, can inhibit lipid rafts and adhesion of tumor cells, which can sensitize them to chemotherapeutic drugs. Clinical studies on simvastatin and lovastatin in a variety of tumors are underway. This article provides a comprehensive review of the role of lipid metabolism in TAMs in tumor progression, and provides new ideas for targeting lipid metabolism in tumor therapy.

Keywords:  Chemotherapy resistance; Immunotherapy; Lipid metabolism; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12944-023-01807-1
Gastroenterology. 2023 Apr 05. pii: S0016-5085(23)00581-4. [Epub ahead of print]

MACROPHAGE-DERIVED OSTEOPONTIN (SPP1) PROTECTS FROM NON-ALCOHOLIC STEATOHEPATITIS.

Hui Han, Xiaodong Ge, Sai Santosh Babu Komakula, Romain Desert, Sukanta Das, Zhuolun Song, Wei Chen, Dipti Athavale, Harriet Gaskell, Daniel Lantvit, Grace Guzman, Natalia Nieto.

  BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning degeneration and fibrosis, all of which increase the risk of progression to end-stage liver disease. Osteopontin (OPN, SPP1) plays an important role in macrophage (MF) biology, but whether macrophage-derived OPN affects NASH progression is unknown.METHODS: We analyzed publicly available transcriptomic datasets from patients with NASH, and used mice with conditional overexpression or ablation of Spp1 in myeloid cells and liver MFs, and fed them a high-fat, fructose and cholesterol diet mimicking the Western diet, to induce NASH.
RESULTS: This study demonstrated that MFs expressing high SPP1 are enriched in patients and mice with NAFLD, and show metabolic but not inflammatory properties. Spp1KI Mye or Spp1KI LvMF conferred protection, whereas OpnΔMye worsened NASH. The protective effect was mediated by induction of arginase-2 (ARG2), which enhanced fatty acid oxidation (FAO) in hepatocytes. Induction of ARG2 stemmed from enhanced production of oncostatin-M (OSM) in MFs from Spp1KI Mye mice. OSM activated STAT3 signaling, which upregulated ARG2. In addition to hepatic effects, Spp1KI Mye also protected through sex-specific extrahepatic mechanisms.
CONCLUSION: MF-derived OPN protects from NASH, by upregulating OSM, which increases ARG2 through STAT3 signaling. Further, the ARG2-mediated increase in FAO reduces steatosis. Therefore, enhancing the OPN-OSM-ARG2 crosstalk between MFs and hepatocytes may be beneficial for NAFLD patients.

Keywords:  arginase 2; inflammation; steatosis

DOI:  https://doi.org/10.1053/j.gastro.2023.03.228
J Invest Dermatol. 2023 Apr 05. pii: S0022-202X(23)01957-7. [Epub ahead of print]

The inhibition of glycolysis in T cells by a Jak inhibitor ameliorates the pathogenesis of allergic contact dermatitis in mice.

Michiko Okamoto, Miyuki Omori-Miyake, Makoto Kuwahara, Masataka Okabe, Mariko Eguchi, Masakatsu Yamashita.

Allergic contact dermatitis (ACD) and atopic dermatitis (AD) develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory drugs, such as Jak inhibitors (jakinibs), would be useful for the long-term management of these diseases due to their profile of favorable adverse effects. However, the efficacy of jakinibs for ACD treatment has not been fully determined under a variety of settings. Therefore, we evaluated the effects of ruxolitinib (Rux), a jakinib for Jak1 and Jak2, using a mouse ACD model. As a result, the lower numbers of immune cells including CD4+ T cells, CD8+ T cells, neutrophils and possibly macrophages as well as milder pathophysiological aspects have been observed in the inflamed skin of ACD with the administration of Rux. In addition, the treatment of differentiating T cells with Rux downregulated the level of IL-2-mediated glycolysis in vitro. Furthermore, symptoms of ACD did not develop in T cell-specific Pgam1-deficient mice whose T cells had no glycolytic capacity. Taken together, our data suggest that the downregulation of glycolysis in T cells by Rux could be an important factor for the suppression of ACD development in mice.

DOI: https://doi.org/10.1016/j.jid.2023.03.1667
Mol Cell. 2023 Apr 06. pii: S1097-2765(23)00167-3. [Epub ahead of print]83(7): 1180-1196.e8

Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA.

Max Paget, Cristhian Cadena, Sadeem Ahmad, Hai-Tao Wang, Tristan X Jordan, Ehyun Kim, Beechui Koo, Shawn M Lyons, Pavel Ivanov, Benjamin tenOever, Xin Mu, Sun Hur.

  Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the RIG-I-like receptors (RLRs), which recognize viral dsRNA and initiate antiviral innate immune responses with the potential of triggering systemic inflammation and immunopathology. Here, we show that stress granules (SGs), molecular condensates that form in response to various stresses including viral dsRNA, play key roles in the controlled activation of RLR signaling. Without the SG nucleators G3BP1/2 and UBAP2L, dsRNA triggers excessive inflammation and immune-mediated apoptosis. In addition to exogenous dsRNA, host-derived dsRNA generated in response to ADAR1 deficiency is also controlled by SG biology. Intriguingly, SGs can function beyond immune control by suppressing viral replication independently of the RLR pathway. These observations thus highlight the multi-functional nature of SGs as cellular "shock absorbers" that converge on protecting cell homeostasis by dampening both toxic immune response and viral replication.

Keywords:  ADAR1; RIG-I-like receptor; antiviral signaling; dsRNA; immune-mediated apoptosis; immunopathology; innate immunity; integrated stress response; molecular condensate; stress granule

DOI:  https://doi.org/10.1016/j.molcel.2023.03.010
mSphere. 2023 Apr 05. e0010423

Host Lipid Transport Protein ORP1 Is Necessary for Coxiella burnetii Growth and Vacuole Expansion in Macrophages.

Baleigh Schuler, Margaret Sladek, Stacey D Gilk.

  Coxiella burnetii is an intracellular bacterium that causes the human disease Q fever. C. burnetii forms a large, acidic Coxiella-containing vacuole (CCV) and uses a type 4B secretion system to secrete effector proteins into the host cell cytoplasm. While the CCV membrane is rich in sterols, cholesterol accumulation in the CCV is bacteriolytic, suggesting that C. burnetii regulation of lipid transport and metabolism is critical for successful infection. The mammalian lipid transport protein ORP1L (oxysterol binding protein-like protein 1 Long) localizes to the CCV membrane and mediates CCV-endoplasmic reticulum (ER) membrane contact sites. ORP1L functions in lipid sensing and transport, including cholesterol efflux from late endosomes and lysosomes (LELs), and the ER. Its sister isoform, ORP1S (oxysterol binding protein-like protein 1 Short) also binds cholesterol but has cytoplasmic and nuclear localization. In ORP1-null cells, we found that CCVs were smaller than in wild-type cells, highlighting the importance of ORP1 in CCV development. This effect was consistent between HeLa cells and murine alveolar macrophages (MH-S cells). CCVs in ORP1-null cells had higher cholesterol content than CCVs in wild-type cells at 4 days of infection, suggesting ORP1 functions in cholesterol efflux from the CCV. While the absence of ORP1 led to a C. burnetii growth defect in MH-S cells, there was no growth defect in HeLa cells. Together, our data demonstrated that C. burnetii uses the host sterol transport protein ORP1 to promote CCV development, potentially by using ORP1 to facilitate cholesterol efflux from the CCV to diminish the bacteriolytic effects of cholesterol. IMPORTANCE Coxiella burnetii is an emerging zoonotic pathogen and bioterrorism threat. No licensed vaccine exists in the United States, and the chronic form of the disease is difficult to treat and potentially lethal. Postinfectious sequelae of C. burnetii infection, including debilitating fatigue, place a significant burden on individuals and communities recovering from an outbreak. C. burnetii must manipulate host cell processes in order to promote infection. Our results establish a link between host cell lipid transport processes and C. burnetii's avoidance of cholesterol toxicity during infection of alveolar macrophages. Elucidating the mechanisms behind bacterial manipulation of the host will yield insight for new strategies to combat this intracellular pathogen.

Keywords:  Coxiella; ORP; cholesterol; intracellular pathogen; membrane contact sites

DOI:  https://doi.org/10.1128/msphere.00104-23
mSphere. 2023 Apr 05. e0062522

Amino Acid Starvation-Induced Glutamine Accumulation Enhances Pneumococcal Survival.

Chengwang Zhang, Yanhong Liu, Haoran An, Xueying Wang, Lina Xu, Haiteng Deng, Songquan Wu, Jing-Ren Zhang, Xiaohui Liu.

  Bacteria are known to cope with amino acid starvation by the stringent response signaling system, which is mediated by the accumulation of the (p)ppGpp alarmones when uncharged tRNAs stall at the ribosomal A site. While a number of metabolic processes have been shown to be regulatory targets of the stringent response in many bacteria, the global impact of amino acid starvation on bacterial metabolism remains obscure. This work reports the metabolomic profiling of the human pathogen Streptococcus pneumoniae under methionine starvation. Methionine limitation led to the massive overhaul of the pneumococcal metabolome. In particular, methionine-starved pneumococci showed a massive accumulation of many metabolites such as glutamine, glutamic acid, lactate, and cyclic AMP (cAMP). In the meantime, methionine-starved pneumococci showed a lower intracellular pH and prolonged survival. Isotope tracing revealed that pneumococci depend predominantly on amino acid uptake to replenish intracellular glutamine but cannot convert glutamine to methionine. Further genetic and biochemical analyses strongly suggested that glutamine is involved in the formation of a "prosurvival" metabolic state by maintaining an appropriate intracellular pH, which is accomplished by the enzymatic release of ammonia from glutamine. Methionine starvation-induced intracellular pH reduction and glutamine accumulation also occurred to various extents under the limitation of other amino acids. These findings have uncovered a new metabolic mechanism of bacterial adaptation to amino acid limitation and perhaps other stresses, which may be used as a potential therapeutic target for infection control. IMPORTANCE Bacteria are known to cope with amino acid starvation by halting growth and prolonging survival via the stringent response signaling system. Previous investigations have allowed us to understand how the stringent response regulates many aspects of macromolecule synthesis and catabolism, but how amino acid starvation promotes bacterial survival at the metabolic level remains largely unclear. This paper reports our systematic profiling of the methionine starvation-induced metabolome in S. pneumoniae. To the best of our knowledge, this represents the first reported bacterial metabolome under amino acid starvation. These data have revealed that the significant accumulation of glutamine and lactate enables S. pneumoniae to form a "prosurvival" metabolic state with a lower intracellular pH, which inhibits bacterial growth for prolonged survival. Our findings have provided insightful information on the metabolic mechanisms of pneumococcal adaptation to nutrient limitation during the colonization of the human upper airway.

Keywords:  Streptococcus pneumoniae; cellular pH; glutamine accumulation; intracellular pH; metabolome; methionine; methionine starvation; survival

DOI:  https://doi.org/10.1128/msphere.00625-22
Microb Pathog. 2023 Apr 01. pii: S0882-4010(23)00129-8. [Epub ahead of print]179 106096

Potential use of the cholesterol transfer inhibitor U18666A as an antiviral drug for research on various viral infections.

Marjan Assefi, Reza Bijan Rostami, Menooa Ebrahimi, Mana Altafi, Pooya M Tehrany, Haider Kamil Zaidan, Bashar Zuhair Talib Al-Naqeeb, Meead Hadi, Saman Yasamineh, Omid Gholizadeh.

  Cholesterol plays critical functions in arranging the biophysical attributes of proteins and lipids in the plasma membrane. For various viruses, an association with cholesterol for virus entrance and/or morphogenesis has been demonstrated. Therefore, the lipid metabolic pathways and the combination of membranes could be targeted to selectively suppress the virus replication steps as a basis for antiviral treatment. U18666A is a cationic amphiphilic drug (CAD) that affects intracellular transport and cholesterol production. A robust tool for investigating lysosomal cholesterol transfer and Ebola virus infection is an androstenolone derived termed U18666A that suppresses three enzymes in the cholesterol biosynthesis mechanism. In addition, U18666A inhibited low-density lipoprotein (LDL)-induced downregulation of LDL receptor and triggered lysosomal aggregation of cholesterol. According to reports, U18666A inhibits the reproduction of baculoviruses, filoviruses, hepatitis, coronaviruses, pseudorabies, HIV, influenza, and flaviviruses, as well as chikungunya and flaviviruses. U18666A-treated viral infections may act as a novel in vitro model system to elucidate the cholesterol mechanism of several viral infections. In this article, we discuss the mechanism and function of U18666A as a potent tool for studying cholesterol mechanisms in various viral infections.

Keywords:  Anti-viral drug; Cholesterol; NPC1; U18666A; Viral infection

DOI:  https://doi.org/10.1016/j.micpath.2023.106096
Clin Immunol. 2023 Apr 04. pii: S1521-6616(23)00101-8. [Epub ahead of print] 109322

Elevated exosome-transferrable lncRNA EPB41L4A-AS1 in CD56bright NK cells is responsible for the impaired NK function in neuroblastoma patients by suppressing cell glycolysis.

Wenjia Chai, Xiaolin Wang, Zhengjing Lu, Shihan Zhang, Wei Wang, Hui Wang, Chenghao Chen, Wei Yang, Haiyan Cheng, Huanmin Wang, Jun Feng, Shen Yang, Qiliang Li, Wenqi Song, Fang Jin, Hui Zhang, Yan Su, Jingang Gui.

  NK cells are one of key immune components in neuroblastoma (NB) surveillance and eradication. Glucose metabolism as a major source of fuel for NK activation is exquisitely regulated. Our data revealed a diminished NK activation and a disproportionally augmented CD56bright subset in NB. Further study showed that NK cells in NB presented with an arrested glycolysis accompanied by an elevated expression of the long noncoding RNA (lncRNA) EPB41L4A-AS1, a known crucial participant in glycolysis regulation, in the CD56bright NK subset. The inhibitory function of lncRNA EPB41L4A-AS1 was recapitulated. Interestingly, our study demonstrated that exosomal lncRNA EPB41L4A-AS1 was transferrable from CD56bright NK to CD56dim NK and was able to quench the glycolysis of target NK. Our data demonstrated that an arrested glycolysis in patient NK cells was associated with an elevated lncRNA in CD56bright NK subset and a cross-talk between heterogeneous NK subsets was achieved by transferring metabolic inhibitory lncRNA through exosomes.

Keywords:  Exosome; Glycolysis; LncRNA; NK cell subset; Neuroblastoma

DOI:  https://doi.org/10.1016/j.clim.2023.109322
Allergy Asthma Immunol Res. 2023 Mar;15(2): 214-230

Oleanolic Acid Acetate Inhibits Mast Cell Activation in Ovalbumin-Induced Allergic Airway Inflammation.

Yeon-Yong Kim, Soyoung Lee, Min-Jong Kim, Mun-Chual Rho, Yong Hyun Jang, Sang-Hyun Kim.

  PURPOSE: Asthma is a complex, heterogeneous chronic inflammatory airway disease with multiple phenotypes. There has been a great progress in managing asthma, but there are still unmet needs for developing uncontrolled asthma treatments. The present study aimed to determine the effectiveness of oleanolic acid acetate (OAA) from Vigna angularis against allergic airway inflammation and the underlying mechanism of action with a focus on mast cells.METHODS: To investigate the effect of OAA in allergic airway inflammation, we used the ovalbumin (OVA)-sensitized and challenged mice. To examine allergic airway inflammation associated with immune responses of mast cell activation in vitro, various types of mast cells were used. Systemic and cutaneous anaphylaxis models were used for mast cell-mediated hyper-responsiveness in vivo.
RESULTS: OAA reduced OVA-induced airway inflammatory responses such as bronchospasm, increase of immune cell infiltration and serum immunoglobulin E and G1 levels. Especially, OAA decreased the mast cell infiltration, and β-hexosaminidase release as a mast cell activation marker in the bronchoalveolar lavage fluid. OAA inhibited mast cell degranulation in mast cell line (RBL-2H3) and primary cells (rat peritoneal mast cell and mouse bone marrow-derived mast cell). Mechanistically, OAA suppressed intracellular signaling pathways including the phosphorylation of phospholipase Cγ and nuclear factor-κB, resulting from the suppression of intracellular calcium influx and pro-inflammatory cytokine expression. Further, oral administration of OAA attenuated mast cell-mediated systemic and cutaneous anaphylaxis.
CONCLUSIONS: Our study showed that OAA can inhibit mast cell-mediated allergic reaction. Consequently, the application of OAA to mast cells for the allergic airway inflammation facilitate a new direction of treating allergic asthma.

Keywords:  Allergy, asthma; Vigna; mast cells; ovalbumin

DOI:  https://doi.org/10.4168/aair.2023.15.2.214
Ann Transl Med. 2023 Mar 15. 11(5): 213

Indole-3-pyruvic acid alleviates rheumatoid arthritis via the aryl hydrocarbon receptor pathway.

Tai Huang, Lin Cheng, Yan Jiang, Lingling Zhang, Long Qian.

  Background: In previous studies, we found that smoking may participate in the pathogenesis of rheumatoid arthritis (RA) via the aryl hydrocarbon receptor (AhR) pathway. However, when we conducted a subgroup analysis, the expression of AhR and CYP1A1 in healthy people was higher than that in RA patients. We considered that endogenous AhR ligands may exist in vivo that activate AhR to play a protective role. Indole-3-pyruvic acid (IPA) is a tryptophan (Trp) metabolite produced by the indole pathway and serves as a ligand of AhR. This study aimed to reveal the effect and mechanism of IPA in RA.Methods: A total of 14 patients with RA and 14 healthy volunteers were enrolled. The differential metabolites were screened with liquid chromatography-mass spectrometry (LC-MS) metabolomics technology. We also treated peripheral blood mononuclear cells (PBMCs) with IPA to evaluate the effect on the differentiation of T helper 17 (Th17) cells or regulatory T (Treg) cells. To determine whether IPA can be used to alleviate RA, we administered IPA to rats with collagen-induced arthritis (CIA). Methotrexate was used as a standard drug for CIA.
Results: When the dose reached 20 mg/kg/d, the severity of CIA was significantly reduced. In vitro experiments verified that IPA inhibited the differentiation of Th17 cells and promoted the differentiation of Treg cells, but this effect was weakened by CH223191.
Conclusions: IPA is a protective factor for RA; it can restore the Th17/Treg cell balance through the AhR pathway, which can alleviate RA.

Keywords:  Indole-3-pyruvic acid (IPA); Th17 cell; Treg cell; aryl hydrocarbon receptor (AhR); rheumatoid arthritis (RA)

DOI:  https://doi.org/10.21037/atm-23-1074