bims-imicid 2023-11-26 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–11–26
thirty-two papers selected by
Dylan Ryan, University of Cambridge

Basic Mechanisms of Immunometabolites in Shaping the Immune Response.
Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.
Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.
Acid ceramidase regulates innate immune memory.
Lactate produced by alveolar type II cells suppresses inflammatory alveolar macrophages in acute lung injury.
NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.
Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.
4-Octyl Itaconate Alleviates Airway Eosinophilic Inflammation by Suppressing Chemokines and Eosinophil Development.
Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4+ T Cells in Aging.
Chikungunya Virus, Metabolism, and Circadian Rhythmicity Interplay in Phagocytic Cells.
Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting mitochondrial DNA synthesis.
Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation.
A metabolic axis of immune intractability.
Cardiac macrophage metabolism in health and disease.
Sirtuins in macrophage immune metabolism: A novel target for cardiovascular disorders.
High Fat Diet-Induced Obesity Dysregulates Splenic B Cell Mitochondrial Activity.
Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.
Particulate matter-induced metabolic recoding of epigenetics in macrophages drives pathogenesis of chronic obstructive pulmonary disease.
Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function.
High Metabolite Concentrations in Portal Venous Blood as a Possible Mechanism for Microbiota Effects on the Immune System, and Western Diseases.
Metaflammation in obesity and its therapeutic targeting.
Retraction Note: NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages.
Metabolic re-programming of keratinocytes in response to contact allergens.
Systemic perturbations in amino acids/amino acid derivatives and tryptophan pathway metabolites associated with murine influenza A virus infection.
Indole-3-Lactic Acid, a Tryptophan Metabolite of Lactiplantibacillus plantarum DPUL-S164, Improved Intestinal Barrier Damage by Activating AhR and Nrf2 Signaling Pathways.
ACSS3 regulates the metabolic homeostasis of epithelial cells and alleviates pulmonary fibrosis.
Live-Cell Imaging Quantifies Changes in Function and Metabolic NADH Autofluorescence During Macrophage-Mediated Phagocytosis of Tumor Cells.
Influence of Breastfeeding on the State of Meta-Inflammation in Obesity-A Narrative Review.
Lactobacillus Intestinalis Primes Epithelial Cells to Suppress Colitis-Related Th17 Response by Host-Microbe Retinoic Acid Biosynthesis.
Shigella flexneri remodeling and consumption of host lipids during infection.
Exploring the Pharmacological Versatility of Ficus Carica: Modulating Classical Immunometabolism and Beyond.
Salt Behind the Scenes of Systemic Lupus Erythematosus and Rheumatoid Arthritis.

J Innate Immun. 2023 Nov 23.

Basic Mechanisms of Immunometabolites in Shaping the Immune Response.

Dylan Gerard Ryan, Christian Graham Peace, Alexander Hooftman.

Background Innate immune cells play a crucial role in responding to microbial infections, but their improper activation can also drive inflammatory disease. For this reason, their activation state is governed by a multitude of factors, including the metabolic state of the cell and, more specifically, the individual metabolites which accumulate intra- and extra-cellularly. This relationship is bidirectional, as innate immune cell activation by pathogen-associated molecular patterns (PAMPs) causes critical changes in cellular metabolism. Summary In this review we describe the emergence of various 'immunometabolites'. We outline the general characteristics of these immunometabolites, the conditions under which they accumulate, and their subsequent impact on immune cells. We delve into well-studied metabolites of recent years, such as succinate and itaconate, as well as newly emerging immunometabolites, such as methylglyoxal. Key Messages We hope that this review may be used as a framework for further studies dissecting the mechanisms by which immunometabolites regulate the immune system, and provide an outlook to harnessing these mechanisms in the treatment of inflammatory diseases.

DOI: https://doi.org/10.1159/000535452
Nat Metab. 2023 Nov 23.

Adipose cDC1s contribute to obesity-associated inflammation through STING-dependent IL-12 production.

Andrew D Hildreth, Eddie T Padilla, Meha Gupta, Yung Yu Wong, Ryan Sun, Akshara R Legala, Timothy E O'Sullivan.

Obesity is associated with chronic low-grade white adipose tissue (WAT) inflammation that can contribute to the development of insulin resistance in mammals. Previous studies have identified interleukin (IL)-12 as a critical upstream regulator of WAT inflammation and metabolic dysfunction during obesity. However, the cell types and mechanisms that initiate WAT IL-12 production remain unclear. Here we show that conventional type 1 dendritic cells (cDC1s) are the cellular source of WAT IL-12 during obesity through analysis of mouse and human WAT single-cell transcriptomic datasets, IL-12 reporter mice and IL-12p70 protein levels by enzyme-linked immunosorbent assay. We demonstrate that cDC1s contribute to obesity-associated inflammation by increasing group 1 innate lymphocyte interferon-γ production and inflammatory macrophage accumulation. Inducible depletion of cDC1s increased WAT insulin sensitivity and systemic glucose tolerance during diet-induced obesity. Mechanistically, endocytosis of apoptotic bodies containing self-DNA by WAT cDC1s drives stimulator of interferon genes (STING)-dependent IL-12 production. Together, these results suggest that WAT cDC1s act as critical regulators of adipose tissue inflammation and metabolic dysfunction during obesity.

DOI: https://doi.org/10.1038/s42255-023-00934-4
Nature. 2023 Nov 22.

Trans-vaccenic acid reprograms CD8+ T cells and anti-tumour immunity.

Hao Fan, Siyuan Xia, Junhong Xiang, Yuancheng Li, Matthew O Ross, Seon Ah Lim, Fan Yang, Jiayi Tu, Lishi Xie, Urszula Dougherty, Freya Q Zhang, Zhong Zheng, Rukang Zhang, Rong Wu, Lei Dong, Rui Su, Xiufen Chen, Thomas Althaus, Peter A Riedell, Patrick B Jonker, Alexander Muir, Gregory B Lesinski, Sarwish Rafiq, Madhav V Dhodapkar, Wendy Stock, Olatoyosi Odenike, Anand A Patel, Joseph Opferman, Takemasa Tsuji, Junko Matsuzaki, Hardik Shah, Brandon Faubert, Shannon E Elf, Brian Layden, B Marc Bissonnette, Yu-Ying He, Justin Kline, Hui Mao, Kunle Odunsi, Xue Gao, Hongbo Chi, Chuan He, Jing Chen.

Diet-derived nutrients are inextricably linked to human physiology by providing energy and biosynthetic building blocks and by functioning as regulatory molecules. However, the mechanisms by which circulating nutrients in the human body influence specific physiological processes remain largely unknown. Here we use a blood nutrient compound library-based screening approach to demonstrate that dietary trans-vaccenic acid (TVA) directly promotes effector CD8+ T cell function and anti-tumour immunity in vivo. TVA is the predominant form of trans-fatty acids enriched in human milk, but the human body cannot produce TVA endogenously1. Circulating TVA in humans is mainly from ruminant-derived foods including beef, lamb and dairy products such as milk and butter2,3, but only around 19% or 12% of dietary TVA is converted to rumenic acid by humans or mice, respectively4,5. Mechanistically, TVA inactivates the cell-surface receptor GPR43, an immunomodulatory G protein-coupled receptor activated by its short-chain fatty acid ligands6-8. TVA thus antagonizes the short-chain fatty acid agonists of GPR43, leading to activation of the cAMP-PKA-CREB axis for enhanced CD8+ T cell function. These findings reveal that diet-derived TVA represents a mechanism for host-extrinsic reprogramming of CD8+ T cells as opposed to the intrahost gut microbiota-derived short-chain fatty acids. TVA thus has translational potential for the treatment of tumours.

DOI: https://doi.org/10.1038/s41586-023-06749-3
Cell Rep. 2023 Nov 22. pii: S2211-1247(23)01470-5. [Epub ahead of print]42(12): 113458

Acid ceramidase regulates innate immune memory.

Nils Rother, Cansu Yanginlar, Geoffrey Prévot, Inge Jonkman, Maaike Jacobs, Mandy M T van Leent, Julia van Heck, Vasiliki Matzaraki, Anthony Azzun, Judit Morla-Folch, Anna Ranzenigo, William Wang, Roy van der Meel, Zahi A Fayad, Niels P Riksen, Luuk B Hilbrands, Rik G H Lindeboom, Joost H A Martens, Michiel Vermeulen, Leo A B Joosten, Mihai G Netea, Willem J M Mulder, Johan van der Vlag, Abraham J P Teunissen, Raphaël Duivenvoorden.

  Innate immune memory, also called "trained immunity," is a functional state of myeloid cells enabling enhanced immune responses. This phenomenon is important for host defense, but also plays a role in various immune-mediated conditions. We show that exogenously administered sphingolipids and inhibition of sphingolipid metabolizing enzymes modulate trained immunity. In particular, we reveal that acid ceramidase, an enzyme that converts ceramide to sphingosine, is a potent regulator of trained immunity. We show that acid ceramidase regulates the transcription of histone-modifying enzymes, resulting in profound changes in histone 3 lysine 27 acetylation and histone 3 lysine 4 trimethylation. We confirm our findings by identifying single-nucleotide polymorphisms in the region of ASAH1, the gene encoding acid ceramidase, that are associated with the trained immunity cytokine response. Our findings reveal an immunomodulatory effect of sphingolipids and identify acid ceramidase as a relevant therapeutic target to modulate trained immunity responses in innate immune-driven disorders.

Keywords:  CP: Immunology; acid ceramidase; epigenetics; immune memory; innate immunity; lipid metabolism; monocytes; nanobiologics; sphingolipids; trained immunity

DOI:  https://doi.org/10.1016/j.celrep.2023.113458
FASEB J. 2023 Dec;37(12): e23316

Lactate produced by alveolar type II cells suppresses inflammatory alveolar macrophages in acute lung injury.

René M Roy, Ayed Allawzi, Nana Burns, Christina Sul, Victoria Rubio, Jessica Graham, Kurt Stenmark, Eva S Nozik, Rubin M Tuder, Christine U Vohwinkel.

  Alveolar inflammation is a hallmark of acute lung injury (ALI), and its clinical correlate is acute respiratory distress syndrome-and it is as a result of interactions between alveolar type II cells (ATII) and alveolar macrophages (AM). In the setting of acute injury, the microenvironment of the intra-alveolar space is determined in part by metabolites and cytokines and is known to shape the AM phenotype. In response to ALI, increased glycolysis is observed in AT II cells, mediated by the transcription factor hypoxia-inducible factor (HIF) 1α, which has been shown to decrease inflammation. We hypothesized that in acute lung injury, lactate, the end product of glycolysis, produced by ATII cells shifts AMs toward an anti-inflammatory phenotype, thus mitigating ALI. We found that local intratracheal delivery of lactate improved ALI in two different mouse models. Lactate shifted cytokine expression of murine AMs toward increased IL-10, while decreasing IL-1 and IL-6 expression. Mice with ATII-specific deletion of Hif1a and mice treated with an inhibitor of lactate dehydrogenase displayed exacerbated ALI and increased inflammation with decreased levels of lactate in the bronchoalveolar lavage fluid; however, all those parameters improved with intratracheal lactate. When exposed to LPS (to recapitulate an inflammatory stimulus as it occurs in ALI), human primary AMs co-cultured with alveolar epithelial cells had reduced inflammatory responses. Taken together, these studies reveal an innate protective pathway, in which lactate produced by ATII cells shifts AMs toward an anti-inflammatory phenotype and dampens excessive inflammation in ALI.

Keywords:  acute lung injury; acute respiratory distress syndrome; alveolar epithelium; alveolar macrophage; glycolysis; hypoxia-inducible factor; lactate

DOI:  https://doi.org/10.1096/fj.202301722R
Int Immunopharmacol. 2023 Nov 20. pii: S1567-5769(23)01584-9. [Epub ahead of print]126 111257

NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.

Yingqian Mi, Mengyan Tang, Qiong Wu, Yinan Wang, Qihui Liu, Pei Zhu, Xiaoyang Xue, Yuntong Liu, Xinyu Chai, Yuyang Hou, Dongmei Yan.

  Bacillus Calmette Guerin (BCG) perfusion is widely used as cancer adjuvant therapy, in which macrophages play an important role. Novel macrophage activated associated protein 1 (NMAAP1), upregulated after BCG's activation, was proved to promote macrophage polarization to the M1 type. We found that BCG could stimulate mice BMDM to the M1 type and kill tumor cells. After the deletion of NMAAP1, the tumor volume of mice became larger, and the number of M1 type macrophages in the tumor decreased significantly. When macrophages were induced into the M1 type, aerobic glycolysis, the Warburg effect manifested in the increased uptake of glucose and the conversion of pyruvate to lactic acid. NMAAP1 could bind with IP3R and regulate macrophage polarization to the M1 type. However, the specific mechanism of how NMAAP1 regulates macrophage polarization towards the M1 type and plays an antitumor role must be clarified. NMAAP1 could promote the release of lactic acid and pyruvate, enhance the glycolysis of macrophages, and affect the expression of HIF-1α. After inhibition of glycolysis by 2-DG and lactic acid generation by FX11, the effects of NMAAP1 promoting macrophage polarization to the antitumor M1 type were weakened. Furthermore, NMAAP1 upregulated the expression of HIF-1α, which is associated with glycolysis. Moreover, the Ca2+/NF-κB pathway regulated HIF-1α expression by NMAAP1 in the macrophages. NMAAP1 promotes the polarization of macrophages towards the M1 type by affecting the Warburg effect stimulated by BCG.

Keywords:  BCG; Glycolysis; Macrophages; NMAAP1; Polarization

DOI:  https://doi.org/10.1016/j.intimp.2023.111257
Biochim Biophys Acta Rev Cancer. 2023 Nov 20. pii: S0304-419X(23)00171-3. [Epub ahead of print] 189022

Hurdle or thruster: Glucose metabolism of T cells in anti-tumour immunity.

Sirui Zhang, Xiaozhen Zhang, Hanshen Yang, Tingbo Liang, Xueli Bai.

  Glucose metabolism is essential for the activation, differentiation and function of T cells and proper glucose metabolism is required to maintain effective T cell immunity. Dysregulation of glucose metabolism is a hallmark of cancer, and the tumour microenvironment (TME2) can create metabolic barriers in T cells that inhibit their anti-tumour immune function. Targeting glucose metabolism is a promising approach to improve the capacity of T cells in the TME. The efficacy of common immunotherapies, such as immune checkpoint inhibitors (ICIs3) and adoptive cell transfer (ACT4), can be limited by T-cell function, and the treatment itself can affect T-cell metabolism. Therefore, understanding the relationship between immunotherapy and T cell glucose metabolism helps to achieve more effective anti-tumour therapy. In this review, we provide an overview of T cell glucose metabolism and how T cell metabolic reprogramming in the TME regulates anti-tumour responses, briefly describe the metabolic patterns of T cells during ICI and ACT therapies, which suggest possible synergistic strategies.

Keywords:  Adoptive cell transfer therapy; Glucose metabolism; Immune checkpoint; Metabolic reprogramming; T cell; Tumour microenvironment

DOI:  https://doi.org/10.1016/j.bbcan.2023.189022
J Immunol. 2023 Nov 22. pii: ji2300155. [Epub ahead of print]

4-Octyl Itaconate Alleviates Airway Eosinophilic Inflammation by Suppressing Chemokines and Eosinophil Development.

Maureen Yin, Ridhima Wadhwa, Jacqueline E Marshall, Caitlin M Gillis, Richard Y Kim, Kamal Dua, Eva M Palsson-McDermott, Padraic G Fallon, Philip M Hansbro, Luke A J O'Neill.

4-Octyl itaconate (4-OI) is a derivative of the Krebs cycle-derived metabolite itaconate and displays an array of antimicrobial and anti-inflammatory properties through modifying cysteine residues within protein targets. We have found that 4-OI significantly reduces the production of eosinophil-targeted chemokines in a variety of cell types, including M1 and M2 macrophages, Th2 cells, and A549 respiratory epithelial cells. Notably, the suppression of these chemokines in M1 macrophages was found to be NRF2-dependent. In addition, 4-OI can interfere with IL-5 signaling and directly affect eosinophil differentiation. In a model of eosinophilic airway inflammation in BALB/c mice, 4-OI alleviated airway resistance and reduced eosinophil recruitment to the lungs. Our findings suggest that itaconate derivatives could be promising therapeutic agents for the treatment of eosinophilic asthma.

DOI: https://doi.org/10.4049/jimmunol.2300155
Adv Sci (Weinh). 2023 Nov 21. e2303664

Extracellular Delivery of Functional Mitochondria Rescues the Dysfunction of CD4+ T Cells in Aging.

Colwyn A Headley, Shalini Gautam, Angelica Olmo-Fontanez, Andreu Garcia-Vilanova, Varun Dwivedi, Anwari Akhter, Alyssa Schami, Kevin Chiem, Russell Ault, Hao Zhang, Hong Cai, Alison Whigham, Jennifer Delgado, Amberlee Hicks, Philip S Tsao, Jonathan Gelfond, Luis Martinez-Sobrido, Yufeng Wang, Jordi B Torrelles, Joanne Turner.

  Mitochondrial dysfunction alters cellular metabolism, increases tissue oxidative stress, and may be principal to the dysregulated signaling and function of CD4+ T lymphocytes in the elderly. In this proof of principle study, it is investigated whether the transfer of functional mitochondria into CD4+ T cells that are isolated from old mice (aged CD4+ T cells), can abrogate aging-associated mitochondrial dysfunction, and improve the aged CD4+ T cell functionality. The results show that the delivery of exogenous mitochondria to aged non-activated CD4+ T cells led to significant mitochondrial proteome alterations highlighted by improved aerobic metabolism and decreased cellular mitoROS. Additionally, mito-transferred aged CD4+ T cells showed improvements in activation-induced TCR-signaling kinetics displaying markers of activation (CD25), increased IL-2 production, enhanced proliferation ex vivo. Importantly, immune deficient mouse models (RAG-KO) showed that adoptive transfer of mito-transferred naive aged CD4+ T cells, protected recipient mice from influenza A and Mycobacterium tuberculosis infections. These findings support mitochondria as targets of therapeutic intervention in aging.

Keywords:  CD4+ T cells; adaptive immunity; aging immunology; immunometabolism; mitochondrial dysfunction

DOI:  https://doi.org/10.1002/advs.202303664
Metabolites. 2023 Nov 11. pii: 1143. [Epub ahead of print]13(11):

Chikungunya Virus, Metabolism, and Circadian Rhythmicity Interplay in Phagocytic Cells.

Linamary Alvarez-García, F Javier Sánchez-García, Mauricio Vázquez-Pichardo, M Maximina Moreno-Altamirano.

  Chikungunya virus (CHIKV) is transmitted to humans by mosquitoes of the genus Aedes, causing the chikungunya fever disease, associated with inflammation and severe articular incapacitating pain. There has been a worldwide reemergence of chikungunya and the number of cases increased to 271,006 in 2022 in the Americas alone. The replication of CHIKV takes place in several cell types, including phagocytic cells. Monocytes and macrophages are susceptible to infection by CHIKV; at the same time, they provide protection as components of the innate immune system. However, in host-pathogen interactions, CHIKV might have the ability to alter the function of immune cells, partly by rewiring the tricarboxylic acid cycle. Some viral evasion mechanisms depend on the metabolic reprogramming of immune cells, and the cell metabolism is intertwined with circadian rhythmicity; thus, a circadian immunovirometabolism axis may influence viral pathogenicity. Therefore, analyzing the interplay between viral infection, circadian rhythmicity, and cellular metabolic reprogramming in human macrophages could shed some light on the new field of immunovirometabolism and eventually contribute to the development of novel drugs and therapeutic approaches based on circadian rhythmicity and metabolic reprogramming.

Keywords:  chikungunya virus; circadian immunovirometabolism; macrophages; metabolic reprogramming; tricarboxylic acid cycle

DOI:  https://doi.org/10.3390/metabo13111143
Free Radic Biol Med. 2023 Nov 20. pii: S0891-5849(23)01115-2. [Epub ahead of print]210 75-84

Ribosome-targeting antibiotic control NLRP3-mediated inflammation by inhibiting mitochondrial DNA synthesis.

Suyuan Liu, Meiling Tan, Jiangxue Cai, Chenxuan Li, Miaoxin Yang, Xiaoxiao Sun, Bin He.

  While antibiotics are designed to target bacteria specifically, most are known to affect host cell physiology. Certain classes of antibiotics have been reported to have immunosuppressive effects, but the underlying mechanisms remain elusive. Here, we show that doxycycline, a ribosomal-targeting antibiotic, effectively inhibited both mitochondrial translation and nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome-mediated caspase-1 activation and interleukin-1β (IL-1β) production in bone-marrow-derived macrophages (BMDMs). In addition, knockdown of mitochondrial methionyl-tRNA formyltransferase (Mtfmt), which is rate limiting for mitochondrial translation, also resulted in the inhibition of NLRP3 inflammasome-mediated caspase-1 activation and IL-1β secretion. Furthermore, both doxycycline treatment and Mtfmt knockdown blocked the synthesis of mitochondrial DNA (mtDNA) and the generation of oxidized mtDNA (Ox-mtDNA), which serves as a ligand for NLRP3 inflammasome activation. In addition, in vivo results indicated that doxycycline mitigated NLRP3 inflammasome-dependent inflammation, including lipopolysaccharide-induced systemic inflammation and endometritis. Taken together, the results unveil the antibiotics targeting the mitoribosome have the ability to mitigate NLRP3 inflammasome activation by inhibiting mitochondrial translation and mtDNA synthesis thus opening up new possibilities for the treatment of NLRP3-related diseases.

Keywords:  Doxycycline; Mitochondrial translation; NLRP3 inflammasome; mtDNA

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.11.014
Antioxidants (Basel). 2023 Nov 02. pii: 1956. [Epub ahead of print]12(11):

Senescent Endothelial Cells Sustain Their Senescence-Associated Secretory Phenotype (SASP) through Enhanced Fatty Acid Oxidation.

Angelica Giuliani, Anna Maria Giudetti, Daniele Vergara, Laura Del Coco, Deborah Ramini, Sara Caccese, Matilde Sbriscia, Laura Graciotti, Gianluca Fulgenzi, Luca Tiano, Francesco Paolo Fanizzi, Fabiola Olivieri, Maria Rita Rippo, Jacopo Sabbatinelli.

  Cellular senescence is closely linked to endothelial dysfunction, a key factor in age-related vascular diseases. Senescent endothelial cells exhibit a proinflammatory phenotype known as SASP, leading to chronic inflammation (inflammaging) and vascular impairments. Albeit in a state of permanent growth arrest, senescent cells paradoxically display a high metabolic activity. The relationship between metabolism and inflammation is complex and varies across cell types and senescence inductions. While some cell types shift towards glycolysis during senescence, others favor oxidative phosphorylation (OXPHOS). Despite the high availability of oxygen, quiescent endothelial cells (ECs) tend to rely on glycolysis for their bioenergetic needs. However, there are limited data on the metabolic behavior of senescent ECs. Here, we characterized the metabolic profiles of young and senescent human umbilical vein endothelial cells (HUVECs) to establish a possible link between the metabolic status and the proinflammatory phenotype of senescent ECs. Senescent ECs internalize a smaller amount of glucose, have a lower glycolytic rate, and produce/release less lactate than younger cells. On the other hand, an increased fatty acid oxidation activity was observed in senescent HUVECs, together with a greater intracellular content of ATP. Interestingly, blockade of glycolysis with 2-deoxy-D-glucose in young cells resulted in enhanced production of proinflammatory cytokines, while the inhibition of carnitine palmitoyltransferase 1 (CPT1), a key rate-limiting enzyme of fatty acid oxidation, ameliorated the SASP in senescent ECs. In summary, metabolic changes in senescent ECs are complex, and this research seeks to uncover potential strategies for modulating these metabolic pathways to influence the SASP.

Keywords:  endothelial cells; fatty acid oxidation; glycolysis; senescence; senescence-associated secretory phenotype

DOI:  https://doi.org/10.3390/antiox12111956
Cancer Immunol Res. 2023 Nov 21.

A metabolic axis of immune intractability.

Dominique C Hinshaw, Meet Patel, Lalita A Shevde.

Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are re-enacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0433
Trends Endocrinol Metab. 2023 Nov 21. pii: S1043-2760(23)00237-0. [Epub ahead of print]

Cardiac macrophage metabolism in health and disease.

Benjamin J Kopecky, Kory J Lavine.

  Cardiac macrophages are essential mediators of cardiac development, tissue homeostasis, and response to injury. Cell-intrinsic shifts in metabolism and availability of metabolites regulate macrophage function. The human and mouse heart contain a heterogeneous compilation of cardiac macrophages that are derived from at least two distinct lineages. In this review, we detail the unique functional roles and metabolic profiles of tissue-resident and monocyte-derived cardiac macrophages during embryonic development and adult tissue homeostasis and in response to pathologic and physiologic stressors. We discuss the metabolic preferences of each macrophage lineage and how metabolism influences monocyte fate specification. Finally, we highlight the contribution of cardiac macrophages and derived metabolites on cell-cell communication, metabolic health, and disease pathogenesis.

Keywords:  HFpEF; cardiac; exercise; infarction; macrophage; metabolism

DOI:  https://doi.org/10.1016/j.tem.2023.10.011
Int J Biol Macromol. 2023 Nov 22. pii: S0141-8130(23)05169-3. [Epub ahead of print] 128270

Sirtuins in macrophage immune metabolism: A novel target for cardiovascular disorders.

Chen-Qin Xu, Ji Li, Zhi-Qiang Liang, Yi-Lang Zhong, Zhi-Hui Zhang, Xue-Qing Hu, Yong-Bing Cao, Jian Chen.

  Sirtuins (SIRT1-SIRT7), as a family of NAD + -dependent protein modifying enzymes, have various catalytic functions, such as deacetylases, dealkalylases, and deribonucleases. The Sirtuins family is directly or indirectly involved in pathophysiological processes such as glucolipid metabolism, oxidative stress, DNA repair and inflammatory response through various pathways and assumes an important role in several cardiovascular diseases such as atherosclerosis, myocardial infarction, hypertension and heart failure. A growing number of studies supports that metabolic and bioenergetic reprogramming directs the sequential process of inflammation. Failure of homeostatic restoration leads to many inflammatory diseases, and that macrophages are the central cells involving the inflammatory response and are the main source of inflammatory cytokines. Regulation of cellular metabolism has emerged as a fundamental process controlling macrophage function, but its exact signaling mechanisms remain to be revealed. Understanding the precise molecular basis of metabolic control of macrophage inflammatory processes may provide new approaches for targeting immune metabolism and inflammation. Here, we provide an update of studies in cardiovascular disease on the function and role of sirtuins in macrophage inflammation and metabolism, as well as drug candidates that may interfere with sirtuins, pointing to future prospects in this field.

Keywords:  Cardiovascular; Immune metabolism; Inflammation; Macrophage; Sirtuin

DOI:  https://doi.org/10.1016/j.ijbiomac.2023.128270
Nutrients. 2023 Nov 17. pii: 4807. [Epub ahead of print]15(22):

High Fat Diet-Induced Obesity Dysregulates Splenic B Cell Mitochondrial Activity.

Anandita Pal, Chien-Te Lin, Ilya Boykov, Emily Benson, Grahame Kidd, Kelsey H Fisher-Wellman, P Darrell Neufer, Saame Raza Shaikh.

  Diet-induced obesity impairs mitochondrial respiratory responses in tissues that are highly metabolically active, such as the heart. However, less is known about the impact of obesity on the respiratory activity of specific cell types, such as splenic B cells. B cells are of relevance, as they play functional roles in obesity-induced insulin resistance, inflammation, and responses to infection. Here, we tested the hypothesis that high-fat-diet (HFD)-induced obesity could impair the mitochondrial respiration of intact and permeabilized splenic CD19+ B cells isolated from C57BL/6J mice and activated ex vivo with lipopolysaccharide (LPS). High-resolution respirometry was used with intact and permeabilized cells. To reveal potential mechanistic targets by which HFD-induced obesity dysregulates B cell mitochondria, we conducted proteomic analyses and 3D serial block face scanning electron microscopy (SBFEM). High-resolution respirometry revealed that intact LPS-stimulated B cells of obese mice, relative to controls, displayed lower ATP-linked, as well as maximal uncoupled, respiration. To directly investigate mitochondrial function, we used permeabilized LPS-stimulated B cells, which displayed increased H2O2 emission and production with obesity. We also examined oxidative phosphorylation efficiency simultaneously, which revealed that oxygen consumption and ATP production were decreased in LPS-stimulated B cells with obesity relative to controls. Despite minimal changes in total respiratory complex abundance, in LPS-stimulated B cells of obese mice, three of the top ten most downregulated proteins were all accessory subunits of respiratory complex I. SBFEM showed that B cells of obese mice, compared to controls, underwent no change in mitochondrial cristae integrity but displayed increased mitochondrial volume that was linked to bioenergetic function. Collectively, these results establish a proof of concept that HFD-induced obesity dysregulates the mitochondrial bioenergetic metabolism of activated splenic B cells.

Keywords:  B cells; high fat diet; mitochondria; obesity; proteome

DOI:  https://doi.org/10.3390/nu15224807
Alzheimers Dement. 2023 Nov 20.

Microglial immunometabolism endophenotypes contribute to sex difference in Alzheimer's disease.

Yuan Hou, Jessica Z K Caldwell, Justin D Lathia, James B Leverenz, Andrew A Pieper, Jeffrey Cummings, Feixiong Cheng.

   INTRODUCTION: The molecular mechanisms that contribute to sex differences, in particular female predominance, in Alzheimer's disease (AD) prevalence, symptomology, and pathology, are incompletely understood.
METHODS: To address this problem, we investigated cellular metabolism and immune responses ("immunometabolism endophenotype") across AD individuals as a function of sex with diverse clinical diagnosis of cognitive status at death (cogdx), Braak staging, and Consortium to Establish a Registry for AD (CERAD) scores using human cortex metabolomics and transcriptomics data from the Religious Orders Study / Memory and Aging Project (ROSMAP) cohort.
RESULTS: We identified sex-specific metabolites, immune and metabolic genes, and pathways associated with the AD diagnosis and progression. We identified female-specific elevation in glycerophosphorylcholine and N-acetylglutamate, which are AD inflammatory metabolites involved in interleukin (IL)-17 signaling, C-type lectin receptor, interferon signaling, and Toll-like receptor pathways. We pinpointed distinct microglia-specific immunometabolism endophenotypes (i.e., lipid- and amino acid-specific IL-10 and IL-17 signaling pathways) between female and male AD subjects. In addition, female AD subjects showed evidence of diminished excitatory neuron and microglia communications via glutamate-mediated immunometabolism.
DISCUSSION: Our results point to new understanding of the molecular basis for female predominance in AD, and warrant future independent validations with ethnically diverse patient cohorts to establish a likely causal relationship of microglial immunometabolism in the sex differences in AD.
HIGHLIGHTS: Sex-specific immune metabolites, gene networks and pathways, are associated with Alzheimer's disease pathogenesis and disease progression. Female AD subjects exhibit microglial immunometabolism endophenotypes characterized by decreased glutamate metabolism and elevated interleukin-10 pathway activity. Female AD subjects showed a shift in glutamate-mediated cell-cell communications between excitatory neurons to microglia and astrocyte.

Keywords:  Alzheimer's disease; endophenotype; glutamate; immunometabolism; microglia; multi-omics; sex difference

DOI:  https://doi.org/10.1002/alz.13546
J Hazard Mater. 2023 Nov 04. pii: S0304-3894(23)02216-1. [Epub ahead of print]464 132932

Particulate matter-induced metabolic recoding of epigenetics in macrophages drives pathogenesis of chronic obstructive pulmonary disease.

Myungkyung Noh, Jeong Yeon Sim, Jisung Kim, Jee Hwan Ahn, Hye-Young Min, Jong-Uk Lee, Jong-Sook Park, Ji Yun Jeong, Jae Young Lee, Shin Yup Lee, Hyo-Jong Lee, Choon-Sik Park, Ho-Young Lee.

  Chronic obstructive pulmonary disease (COPD) is a group of illnesses associated with unresolved inflammation in response to toxic environmental stimuli. Persistent exposure to PM is a major risk factor for COPD, but the underlying mechanism remains unclear. Using our established mouse model of PM-induced COPD, we find that repeated PM exposure provokes macrophage-centered chronic inflammation and COPD development. Mechanistically, chronic PM exposure induces transcriptional downregulation of HAAO, KMO, KYNU, and QPRT in macrophages, which are the enzymes of de novo NAD+ synthesis pathway (kynurenine pathway; KP), via elevated chromatin binding of the CCCTC-binding factor (CTCF) near the transcriptional regulatory regions of the enzymes. Subsequent reduction of NAD+ and SIRT1 function increases histone acetylation, resulting in elevated expression of pro-inflammatory genes in PM-exposed macrophages. Activation of SIRT1 by nutraceutical resveratrol mitigated PM-induced chronic inflammation and COPD development. In agreement, increased levels of histone acetylation and decreased expression of KP enzymes were observed in pulmonary macrophages of COPD patients. We newly provide an evidence that dysregulated NAD+ metabolism and consecutive SIRT1 deficiency significantly contribute to the pathological activation of macrophages during PM-mediated COPD pathogenesis. Additionally, targeting PM-induced intertwined metabolic and epigenetic reprogramming in macrophages is an effective strategy for COPD treatment.

Keywords:  COPD; Chronic inflammation; Histone acetylation; Macrophage; NAD(+) metabolism; Particulate matter; SIRT activity

DOI:  https://doi.org/10.1016/j.jhazmat.2023.132932
J Biol Chem. 2023 Nov 22. pii: S0021-9258(23)02516-4. [Epub ahead of print] 105488

Overexpression of AMPKγ2 increases AMPK signaling to augment human T cell metabolism and function.

Erica L Braverman, Margaret A McQuaid, Herbert Schuler, Mengtao Qin, Sophia Hani, Keli Hippen, Darlene A Monlish, Andrea K Dobbs, Manda J Ramsey, Felicia Kemp, Christopher Wittmann, Archana Ramgopal, Harrison Brown, Bruce Blazar, Craig A Byersdorfer.

Cellular therapies are currently employed to treat a variety of disease processes. For T cell-based therapies, success often relies on the metabolic fitness of the T cell product, where cells with enhanced metabolic capacity demonstrate improved in vivo efficacy. AMP-activated protein kinase (AMPK) is a cellular energy sensor which combines environmental signals with cellular energy status to enforce efficient and flexible metabolic programming. We hypothesized that increasing AMPK activity in human T cells would augment their oxidative capacity, creating an ideal product for adoptive cellular therapies. Lentiviral transduction of the regulatory AMPKγ2 subunit stably enhanced intrinsic AMPK signaling and promoted mitochondrial respiration with increased basal oxygen consumption rates (OCR), higher maximal OCR, and augmented spare respiratory capacity. These changes were accompanied by increased proliferation and inflammatory cytokine production, particularly within restricted glucose environments. Introduction of AMPKγ2 into bulk CD4 T cells decreased RNA expression of canonical Th2 genes, including the cytokines IL-4 and IL-5, while introduction of AMPKγ2 into individual Th subsets universally favored pro-inflammatory cytokine production and a down-regulation of IL-4 production in Th2 cells. When AMPKγ2 was overexpressed in regulatory T cells (Treg), both in vitro proliferation and suppressive capacity increased. Together, these data suggest that augmenting intrinsic AMPK signaling via overexpression of AMPKγ2 can improve the expansion and functional potential of human T cells for use in a variety of adoptive cellular therapies.

DOI: https://doi.org/10.1016/j.jbc.2023.105488
J Allergy Clin Immunol. 2023 Nov 20. pii: S0091-6749(23)01477-X. [Epub ahead of print]

High Metabolite Concentrations in Portal Venous Blood as a Possible Mechanism for Microbiota Effects on the Immune System, and Western Diseases.

Quanbo Wang, Charles R Mackay.

  We show that the gut bacterial metabolites, short chain fatty acids (SCFAs), are present at exceptionally high concentrations in the portal venous circulation, particularly small blood vessels that emanate from colonic mucosa. Likely, many other metabolites will be present at high concentrations. Herein we propose a model for immune conditioning, whereby metabolites such as butyrate affect immune cells as they pass through the portal venous system. Deficiency of SCFA would lead to pro-inflammatory immune cell skewing through insufficient G-protein coupled receptor (GPCR) signalling, or lack of histone deacetylase (HDAC) inhibition. Such pro-inflammatory immune cells may travel to tissues such as the brain, the lung, the kidney etc and promote disease. This model helps explain how the gut microbiome may be affecting peripheral immune cells, and consequently Western lifestyle diseases, most of which are immune based, in tissues remote from the gut.

Keywords:  Gut microbiota; Western lifestyle diseases; portal vein; short chain fatty acids

DOI:  https://doi.org/10.1016/j.jaci.2023.10.029
Sci Transl Med. 2023 Nov 22. 15(723): eadf9382

Metaflammation in obesity and its therapeutic targeting.

Michael W Schleh, Heather L Caslin, Jamie N Garcia, Mona Mashayekhi, Gitanjali Srivastava, Anna B Bradley, Alyssa H Hasty.

Obesity-associated inflammation is a systemic process that affects all metabolic organs. Prominent among these is adipose tissue, where cells of the innate and adaptive immune system are markedly changed in obesity, implicating these cells in a range of processes linking immune memory to metabolic regulation. Furthermore, weight loss and weight cycling have unexpected effects on adipose tissue immune populations. Here, we review the current literature on the roles of various immune cells in lean and obese adipose tissue. Within this context, we discuss pharmacological and nonpharmacological approaches to obesity treatment and their impact on systemic inflammation.

DOI: https://doi.org/10.1126/scitranslmed.adf9382
Nat Med. 2023 Nov 24.

Retraction Note: NOX4-dependent fatty acid oxidation promotes NLRP3 inflammasome activation in macrophages.

Jong-Seok Moon, Kiichi Nakahira, Kuei-Pin Chung, Gina M DeNicola, Michael Jakun Koo, Maria A Pabón, Kristen T Rooney, Joo-Heon Yoon, Stefan W Ryter, Heather Stout-Delgado, Augustine M K Choi.

DOI: https://doi.org/10.1038/s41591-023-02723-8
Contact Dermatitis. 2023 Nov 20.

Metabolic re-programming of keratinocytes in response to contact allergens.

Mandy Menzel, Veronika Mraz, Helen Vaher, Carsten Geisler, Charlotte Menné Bonefeld.

   BACKGROUND: Allergic contact dermatitis (ACD) is a common skin disease caused by the recognition of haptens by the immune system. Keratinocytes play an important role in the initiation and facilitation of inflammatory responses in ACD. Immune responses are associated with major changes in metabolism. However, metabolic re-programming is not well studied in ACD; specifically, knowledge of metabolic alterations in structural cells is lacking.
METHODS: Metabolic re-programming in ACD was studied using publicly available transcriptome datasets. Primary pooled keratinocytes and a keratinocyte cell line (HaCaT) were stimulated with contact allergens, and inflammatory responses and expression of metabolic markers were measured by qPCR and flow cytometry, respectively.
RESULTS: ACD is characterized by metabolic re-programming with a metabolic profile similar to atopic dermatitis. Exposure to contact allergens causes a wide array of metabolic alterations. Stimulation of keratinocytes with contact allergens induced inflammatory responses typical for ACD and was associated with an up-regulation of proteins representative for glucose uptake, fatty acid metabolism, oxidative phosphorylation and to some extent arginine biosynthesis. Changes in these metabolic pathways were also observed when comparing lesional with non-lesional contact dermatitis skin.
CONCLUSIONS: ACD is, similarly to other inflammatory skin diseases, characterized by metabolic re-programming. Contact allergen exposure induces expression of a wide array of metabolic pathways, which is at least in part mediated through metabolic re-programming of keratinocytes.

Keywords:  allergic contact dermatitis; keratinocytes; metabolic re-programming

DOI:  https://doi.org/10.1111/cod.14462
Virol J. 2023 Nov 21. 20(1): 270

Systemic perturbations in amino acids/amino acid derivatives and tryptophan pathway metabolites associated with murine influenza A virus infection.

Huda A M Al-Shalan, Lu Zhou, Zhifan Dong, Penghao Wang, Philip K Nicholls, Berin Boughton, Philip A Stumbles, Wayne K Greene, Bin Ma.

   BACKGROUND: Influenza A virus (IAV) is the only influenza virus causing flu pandemics (i.e., global epidemics of flu disease). Influenza (the flu) is a highly contagious disease that can be deadly, especially in high-risk groups. Worldwide, these annual epidemics are estimated to result in about 3 to 5 million cases of severe illness and in about 290,000 to 650,000 respiratory deaths. We intend to reveal the effect of IAV infection on the host's metabolism, immune response, and neurotoxicity by using a mouse IAV infection model.
METHODS: 51 metabolites of murine blood plasma (33 amino acids/amino acid derivatives (AADs) and 18 metabolites of the tryptophan pathway) were analyzed by using Ultra-High-Performance Liquid Chromatography-Mass Spectrometry with Electrospray Ionization at the acute (7 days post-infection (dpi)), resolution (14 dpi), and recovery (21 dpi) stages of the virus infection in comparison with controls.
RESULTS: Among the 33 biogenic amino acids/AADs, the levels of five amino acids/AADs (1-methylhistidine, 5-oxoproline, α-aminobutyric acid, glutamine, and taurine) increased by 7 dpi, whereas the levels of ten amino acids/AADs (4-hydroxyproline, alanine, arginine, asparagine, cysteine, citrulline, glycine, methionine, proline, and tyrosine) decreased. By 14 dpi, the levels of one AAD (3-methylhistidine) increased, whereas the levels of five amino acids/AADs (α-aminobutyric acid, aminoadipic acid, methionine, threonine, valine) decreased. Among the 18 metabolites from the tryptophan pathway, the levels of kynurenine, quinolinic acid, hydroxykynurenine increased by 7 dpi, whereas the levels of indole-3-acetic acid and nicotinamide riboside decreased.
CONCLUSIONS: Our data may facilitate understanding the molecular mechanisms of host responses to IAV infection and provide a basis for discovering potential new mechanistic, diagnostic, and prognostic biomarkers and therapeutic targets for IAV infection.

Keywords:  Amino acids; Immunometabolism; Infection; Influenza; Influenza A virus; Metabolites; Neurotoxicity; Tryptophan pathway

DOI:  https://doi.org/10.1186/s12985-023-02239-0
J Agric Food Chem. 2023 Nov 23.

Indole-3-Lactic Acid, a Tryptophan Metabolite of Lactiplantibacillus plantarum DPUL-S164, Improved Intestinal Barrier Damage by Activating AhR and Nrf2 Signaling Pathways.

Arong Wang, Cheng Guan, Tieqi Wang, Guangqing Mu, Yanfeng Tuo.

  A growing body of evidence suggests that microbial tryptophan metabolites play a crucial role in maintaining intestinal barrier stability and modulating host immunity. Our previous study showed that the Lactiplantibacillus plantarum (L. plantarum ) DPUL-S164 intervention in mice with a high tryptophan (Trp) diet promotes indole-3-lactic acid (ILA) production in the mice's intestinal tract and ameliorates dextran sodium sulfate(DSS)-induced intestinal barrier damage in mice. In this study, we used the HT-29 cell monolayer model to evaluate the effect of the L. plantarum DPUL-S164 Trp metabolites (DPUL-S164-TM) on the intestinal barrier. We found that L. plantarum DPUL-S164-TM alleviated lipopolysaccharide (LPS)-induced intestinal barrier damage and inflammation of the HT-29 cell monolayer by promoting the expression of tight junction proteins (ZO-1, occludin, claudin1), activating the AhR and Nrf2 signaling pathways, and inhibiting the NF-κB signaling pathway. We found that the promotion of tight junction protein expression and the activation of the Nrf2 signaling pathway by L. plantarum DPUL-S164-TM were dependent on the AhR expression of HT-29 cells. Additionally, L. plantarum DPUL-S164-TM showed a dramatic increase in the ILA content. Therefore, we inferred that ILA in L. plantarum DPUL-S164-TM plays a key role in improving the intestinal barrier function and alleviating inflammation.

Keywords:  Lactiplantibacillus plantarum; aryl hydrocarbon receptor; indole-3-lactic acid; intestinal barrier function; tryptophan-derived metabolites

DOI:  https://doi.org/10.1021/acs.jafc.3c06183
Biochim Biophys Acta Mol Basis Dis. 2023 Nov 16. pii: S0925-4439(23)00326-5. [Epub ahead of print]1870(2): 166960

ACSS3 regulates the metabolic homeostasis of epithelial cells and alleviates pulmonary fibrosis.

Lan Wang, Hongmei Yuan, Wenwen Li, Peishuo Yan, Mengxia Zhao, Zhongzheng Li, Huabin Zhao, Shenghui Wang, Ruyan Wan, Yajun Li, Juntang Yang, Xin Pan, Ivan Rosas, Guoying Yu.

  Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease of unknown etiology. The emerging evidence demonstrates that metabolic homeostatic imbalance caused by repetitive injuries of the alveolar epithelium is the potential pathogenesis of IPF. Proteomic analysis identified that Acetyl-CoA synthetase short chain family member 3 (ACSS3) expression was decreased in IPF patients and mice with bleomycin-induced fibrosis. ACSS3 participated in lipid and carbohydrate metabolism. Increased expression of ACSS3 downregulated carnitine palmitoyltransferase 1A (CPT-1A) and resulted in the accumulation of lipid droplets, while enhanced glycolysis which led to an increase in extracellular lactic acid levels in A549 cells. ACSS3 increases the production of succinyl-CoA through propionic acid metabolism, and decreases the generation of acetyl-CoA and ATP in alveolar epithelial cells. Overexpression of Acss3 inhibited the excessive deposition of ECM and attenuated the ground-glass opacity which determined by micro-CT in vivo. In a nutshell, our findings demonstrate that ACSS3 decreased the fatty acid oxidation through CPT1A deficiency and enhanced anaerobic glycolysis, this metabolic reprogramming deactivate the alveolar epithelial cells by lessen mitochondrial fission and fusion, increase of ROS production, suppression of mitophagy, promotion of apoptosis, suggesting that ACSS3 might be potential therapeutic target in pulmonary fibrosis.

Keywords:  ACSS3; Metabolic reprogramming; Mitochondrial dysfunction; Pulmonary fibrosis

DOI:  https://doi.org/10.1016/j.bbadis.2023.166960
Immunol Invest. 2023 Nov 24. 1-14

Live-Cell Imaging Quantifies Changes in Function and Metabolic NADH Autofluorescence During Macrophage-Mediated Phagocytosis of Tumor Cells.

Shelby N Bess, Matthew J Igoe, Timothy J Muldoon.

   BACKGROUND: The immune system has evolved to detect foreign antigens and deliver coordinated responses, while minimizing "friendly fire." Until recently, studies investigating the behavior of immune cells were limited to static in vitro measurements. Although static measurements allow for real-time imaging, results are often difficult to translate to an in vivo setting. Multiphoton microscopy is an emerging method to capture spatial information on subcellular events and characterize the local microenvironment. Previous studies have shown that multiphoton microscopy can monitor changes in single-cell macrophage heterogeneity during differentiation. Therefore, there is a need to use multiphoton microscopy to monitor molecular interactions during immunological activities like phagocytosis. Here we investigate the correlation between phagocytic function and changes in endogenous optical reporters during phagocytosis.
METHODS: In vitro autofluorescence imaging of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) was used to detect metabolic changes in macrophages during phagocytosis. More specifically, optical redox ratio, mean NADH fluorescence lifetime and ratio of free to protein-bound NADH were used to quantify changes in metabolism.
RESULTS: Results show that IFN-γ (M1) macrophages showed decreased optical redox ratios and mean NADH lifetime while phagocytosing immunogenic cancer cells compared to metastatic cells. To validate phagocytic function, a fluorescence microscopy-based protocol using a pH-sensitive fluorescent probe was used. Results indicate that M0 and M1 macrophages show similar trends in phagocytic potential.
CONCLUSION: Overall, this work demonstrates that in vitro multiphoton imaging can be used to longitudinally track changes in phagocytosis and endogenous metabolic cofactors.

Keywords:  Macrophages; metabolism; phagocytosis; single-cell imaging

DOI:  https://doi.org/10.1080/08820139.2023.2284369
Curr Issues Mol Biol. 2023 Nov 11. 45(11): 9003-9018

Influence of Breastfeeding on the State of Meta-Inflammation in Obesity-A Narrative Review.

Dominika Mazur, Małgorzata Satora, Anna K Rekowska, Zuzanna Kabała, Aleksandra Łomża, Żaneta Kimber-Trojnar, Bożena Leszczyńska-Gorzelak.

  Obesity has become an emerging health issue worldwide that continues to grow in females of reproductive age as well. Obesity, as a multisystem and chronic disease, is associated with metabolic inflammation, which is defined as chronic low-grade systemic inflammation mediated by, i.a., adipose tissue macrophages. Lactation has been proven to have a beneficial influence on maternal health and could help restore metabolic balance, especially in the state of maternal obesity. In this review, we aimed to analyze the influence of breastfeeding on chronic low-grade meta-inflammation caused by obesity. We performed a comprehensive literature review using the PubMed, Science Direct, and Google Scholar electronic databases. For this purpose, we searched for "metabolic inflammation"; "meta-inflammation"; "obesity"; "breastfeeding"; "fetal programming"; "energy metabolism"; "postpartum"; "immunity"; "immune system"; and "inflammation" keyword combinations. While the clinical impact of breastfeeding on maternal and offspring health is currently well known, we decided to gain insight into more specific metabolic effects of adiposity, lipid, and glucose homeostasis, and immunological effects caused by the activity of cytokines, macrophages, and other immune system cells. Further research on the immunological and metabolic effects of breastfeeding in obese patients is key to understanding and potentially developing obesity therapeutic strategies.

Keywords:  breastfeeding; energy metabolism; immunology; metabolic inflammation; metabolic programming; obesity

DOI:  https://doi.org/10.3390/cimb45110565
Adv Sci (Weinh). 2023 Nov 20. e2303457

Lactobacillus Intestinalis Primes Epithelial Cells to Suppress Colitis-Related Th17 Response by Host-Microbe Retinoic Acid Biosynthesis.

Qi-Wen Wang, Ding-Jia-Cheng Jia, Jia-Min He, Yong Sun, Yun Qian, Qi-Wei Ge, Ya-Dong Qi, Qing-Yi Wang, Ying-Ying Hu, Lan Wang, Yan-Fei Fang, Hui-Qin He, Man Luo, Li-Jun Feng, Jian-Min Si, Zhang-Fa Song, Liang-Jing Wang, Shu-Jie Chen.

  Gut microbiome is integral to the pathogenesis of ulcerative colitis. A novel probiotic Lactobacillus intestinalis (L. intestinalis) exerts a protective effect against dextran sodium sulfate-induced colitis in mice. Based on flow cytometry, colitis-associated Th17 cells are the target of L. intestinalis, which is supported by the lack of protective effects of L. intestinalis in T cell-null Rag1-/- mice or upon anti-IL-17-A antibody-treated mice. Although L. intestinalis exerts no direct effect on T cell differentiation, it decreases C/EBPA-driven gut epithelial SAA1 and SAA2 production, which in turn impairs Th17 cell differentiation. Cometabolism of L. intestinalis ALDH and host ALDH1A2 contributed to elevated biosynthesis of retinoic acid (RA), which accounts for the anti-colitis effect in RAR-α -mediated way. In a cohort of ulcerative colitis patients, it is observed that fecal abundance of L. intestinalis is negatively associated with the C/EBPA-SAA1/2-Th17 axis. Finally, L. intestinalis has a synergistic effect with mesalazine in alleviating murine colitis. In conclusion, L. intestinalis and associated metabolites, RA, have potential therapeutic effects for suppressing colonic inflammation by modulating the crosstalk between intestinal epithelia and immunity.

Keywords:  Th17; colitis; microbes; retinoic acid

DOI:  https://doi.org/10.1002/advs.202303457
J Bacteriol. 2023 Nov 22. e0032023

Shigella flexneri remodeling and consumption of host lipids during infection.

Alice Ascari, Sonja Frölich, Maoge Zang, Elizabeth N H Tran, Danny W Wilson, Renato Morona, Bart A Eijkelkamp.

   IMPORTANCE: Bacterial pathogens have vastly distinct sites that they inhabit during infection. This requires adaptation due to changes in nutrient availability and antimicrobial stress. The bacterial surface is a primary barrier, and here, we show that the bacterial pathogen Shigella flexneri increases its surface decorations when it transitions to an intracellular lifestyle. We also observed changes in bacterial and host cell fatty acid homeostasis. Specifically, intracellular S. flexneri increased the expression of their fatty acid degradation pathway, while the host cell lipid pool was significantly depleted. Importantly, bacterial proliferation could be inhibited by fatty acid supplementation of host cells, thereby providing novel insights into the possible link between human malnutrition and susceptibility to S. flexneri.

Keywords:  O antigen; Shigella flexneri; fatty acids; lipid droplets; lipid homeostasis; lipopolysaccharide

DOI:  https://doi.org/10.1128/jb.00320-23
Pharmacol Res. 2023 Nov 21. pii: S1043-6618(23)00366-3. [Epub ahead of print] 107010

Exploring the Pharmacological Versatility of Ficus Carica: Modulating Classical Immunometabolism and Beyond.

Amene Saghazadeh.

  The burden of metabolic disorders is alarmingly increasing globally. On the other hand, sustainability is the key project of the 21st century. Natural products offer a coherent option for the complementary management of both these challenges. Ficus carica (FC), commonly known as the fig fruit, has an experimentally proven potency for the modulation of cell cycle, immunity, inflammation, metabolism, and oxidative stress. Here, we review the potential of FC-derived products (FCDP) in slowing down the progression of cancers, acute/chronic inflammation-related conditions, infections, metabolic disorders, toxicities, neurological and neuromuscular diseases, gastrointestinal disorders, vascular diseases, and skin-stressing conditions, as well as, in boosting normal healthy functions of the endocrine, immune, metabolic, and nervous systems. It reveals a variety of cellular and molecular targets for FCDP: cytokines (TNF-α, IL-1β, IL-6, IL-10, IL-12, IL-18, IFN-γ), chemokines (CCL2), other inflammatory mediators (CRP, PGE2), immune receptors (TLR-2, TLR-4, FcεRI), oxidative stress-related markers (SOD, GSH, MDA, GPx, catalase, ROS, NO, protein carbonyls), kinases (MAPKs, hexokinase, G6Pase, FBPase, PEPCK, Akt, AMPK, GSK3, CDKs), other enzymes (COX-2, iNOS, MMPs, caspases), growth factors/receptors (VEGF, EGFR), hormones (DHEAS, prolactin, GnRH, FSH, LH, estradiol, DHT, insulin), cell death-related markers (Bcl-2, Bax, Bak, FasL, gasdermins, cytochrome C), glucose transporter protein (Glut4), and transcription factors (NF-κB, HNF-4α, Foxo, PGC-1α, PPAR-γ, C/EBP-α, CREB, NFATC1, STAT3). FCDP cause both activation and inhibition of AMPK, MAPK, and NF-κB signaling to confer condition-specific advantages. Such a broad-range activity might be attributed to different mechanisms of action of FCDP in modulating functions within the classical immunometabolic system, but also beyond.

Keywords:  Ficus carica; Immunometabolism; Inflammation; Metabolism; Signaling; Targeted therapy

DOI:  https://doi.org/10.1016/j.phrs.2023.107010
Curr Nutr Rep. 2023 Nov 18.

Salt Behind the Scenes of Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Baris Afsar, Rengin Elsurer Afsar.

   PURPOSE OF REVIEW: Sodium is vital for human health. High salt intake is a global health problem and is associated with cardiovascular morbidity and mortality. Recent evidence suggests that both innate and adaptive immune systems are affected by sodium. In general, excess salt intake drives immune cells toward a pro-inflammatory phenotype. The incidence of autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), is steadily increasing. As excess salt induces a pro-inflammatory state, increased salt intake may have impacts on autoimmune diseases. The relationship between salt intake and autoimmune diseases is most widely studied in patients with SLE or RA. This review aimed to summarize the relationship between salt intake and SLE and RA.
RECENT FINDINGS: Most, but not all, of these studies showed that high salt intake might promote SLE by M1 macrophage shift, increase in Th17/Treg cell ratio, activation of dendritic and follicular helper T cells, and increased secretion of pro-inflammatory cytokines. In RA, apart from driving immune cells toward a pro-inflammatory state, high salt intake also influences cellular signaling pathways, including receptor activator of nuclear factor κB ligand (RANKL), Rho GTPases, and MAPK (mitogen-activated protein kinase). There is now sufficient evidence that excess salt intake may be related to the development and progression of SLE and RA, although there are still knowledge gaps. More studies are warranted to further highlight the relationship between excess salt intake, SLE, and RA. Salt intake may affect cell types and pro-inflammatory cytokines and signaling pathways associated with the development and progression of systemic lupus erythematosus and rheumatoid arthritis. Bcl-6 B-cell lymphoma, 6 Erk extracellular signal-regulated kinases, IFN-γ interferon-gamma, JNK c-Jun N-terminal kinase, IL-4 interleukin 4, IL-6 interleukin 6, MAPK mitogen-activated protein kinase, STAT signal transducer and activator of transcription, Tnf-α tumor necrosis factor, Treg T regulatory cell.

Keywords:  Autoimmune disease; Rheumatoid arthritis; Salt; Sodium; Systemic lupus erythematosus

DOI:  https://doi.org/10.1007/s13668-023-00509-5