bims-imicid 2023-10-01 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023‒10‒01
twenty-six papers selected by
Dylan Ryan, University of Cambridge

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.
Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.
Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation.
Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models.
Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1α to the Nrf2 Pathway.
Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury.
Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections.
The immunometabolic reprogramming of microglia in Alzheimer's disease.
Antigen priming induces functional reprogramming in iNKT cells via metabolic and epigenetic regulation: An insight into iNKT cell-based anti-tumor immunotherapy.
Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.
Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response.
New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease.
Glycolytic shift during West Nile virus infection provides new therapeutic opportunities.
Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis.
Leishmania mexicana centrin knockout parasites promote M1-polarizing metabolic changes.
Anti-Necroptotic Effects of Itaconate and its Derivatives.
Exercise changes the intrahepatic immune cell profile and inhibits the progression of nonalcoholic steatohepatitis in a mouse model.
Identification of potential hub genes linked to immune and metabolic alterations in postoperative systemic inflammatory dysregulation.
Low dietary fiber intake impairs small intestinal Th17 and intraepithelial T cell development over generations.
Mild to moderate post-COVID-19 alters markers of lymphocyte activation, exhaustion, and immunometabolic responses that can be partially associated by physical activity level- an observational sub-analysis fit- COVID study.
IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice.
Plasma cell differentiation, antibody quality, and initial germinal center B cell population depend on glucose influx rate.
Mitochondrial dynamics modulate the allergic inflammation in a murine model of allergic rhinitis.
A tryptophan metabolite made by a gut microbiome eukaryote induces pro-inflammatory T cells.
Role of sphingosine 1-phosphate (S1P) in sepsis-associated intestinal injury.
Phenotypic and functional characteristics of murine CD11c+ B cells which is suppressed by metformin.

PLoS Pathog. 2023 Sep 25. 19(9): e1011658

Choline metabolism underpins macrophage IL-4 polarization and RELMα up-regulation in helminth infection.

Peyman Ghorbani, Sang Yong Kim, Tyler K T Smith, Lucía Minarrieta, Victoria Robert-Gostlin, Marisa K Kilgour, Maja Ilijevska, Irina Alecu, Shayne A Snider, Kaitlyn D Margison, Julia R C Nunes, Daniel Woo, Ciara Pember, Conor O'Dwyer, Julie Ouellette, Pavel Kotchetkov, Julie St-Pierre, Steffany A L Bennett, Baptiste Lacoste, Alexandre Blais, Meera G Nair, Morgan D Fullerton.

Type 2 cytokines like IL-4 are hallmarks of helminth infection and activate macrophages to limit immunopathology and mediate helminth clearance. In addition to cytokines, nutrients and metabolites critically influence macrophage polarization. Choline is an essential nutrient known to support normal macrophage responses to lipopolysaccharide; however, its function in macrophages polarized by type 2 cytokines is unknown. Using murine IL-4-polarized macrophages, targeted lipidomics revealed significantly elevated levels of phosphatidylcholine, with select changes to other choline-containing lipid species. These changes were supported by the coordinated upregulation of choline transport compared to naïve macrophages. Pharmacological inhibition of choline metabolism significantly suppressed several mitochondrial transcripts and dramatically inhibited select IL-4-responsive transcripts, most notably, Retnla. We further confirmed that blocking choline metabolism diminished IL-4-induced RELMα (encoded by Retnla) protein content and secretion and caused a dramatic reprogramming toward glycolytic metabolism. To better understand the physiological implications of these observations, naïve or mice infected with the intestinal helminth Heligmosomoides polygyrus were treated with the choline kinase α inhibitor, RSM-932A, to limit choline metabolism in vivo. Pharmacological inhibition of choline metabolism lowered RELMα expression across cell-types and tissues and led to the disappearance of peritoneal macrophages and B-1 lymphocytes and an influx of infiltrating monocytes. The impaired macrophage activation was associated with some loss in optimal immunity to H. polygyrus, with increased egg burden. Together, these data demonstrate that choline metabolism is required for macrophage RELMα induction, metabolic programming, and peritoneal immune homeostasis, which could have important implications in the context of other models of infection or cancer immunity.

DOI: https://doi.org/10.1371/journal.ppat.1011658
Front Immunol. 2023 ;14 1243548

Mitochondrial PGAM5-Drp1 signaling regulates the metabolic reprogramming of macrophages and regulates the induction of inflammatory responses.

Bo-Ram Bang, Haruka Miki, Young Jun Kang.

  Macrophages play a critical role in the regulation of inflammation and tissue homeostasis. In addition to their vital functions for cell survival and physiology, mitochondria play a crucial role in innate immunity as a platform for the induction of inflammatory responses by regulating cell signaling and dynamics. Dynamin-related protein 1 (Drp1) plays a role in the induction of inflammatory responses and the subsequent development of various diseases. PGAM5 (phosphoglycerate mutase member 5) is a mitochondrial outer membrane phosphatase that dephosphorylates its substrate, Drp1. Previous studies showed that PGAM5 regulates the phosphorylation of Drp1 for the activation of NKT cells and T cells. However, it is not clear how PGAM5 regulates Drp1 activity for the induction of inflammation in macrophages. Here, we demonstrate that PGAM5 activity regulates the dephosphorylation of Drp1 in macrophages, leading to the induction of proinflammatory responses in macrophages. In TLR signaling, PGAM5 regulates the expression and production of inflammatory cytokines by regulating the activation of downstream signaling pathways, including the NF-κB and MAPK pathways. Upon LPS stimulation, PGAM5 interacts with Drp1 to form a complex, leading to the production of mtROS. Furthermore, PGAM5-Drp1 signaling promotes the polarization of macrophages toward a proinflammatory phenotype. Our study further demonstrates that PGAM5-Drp1 signaling promotes metabolic reprogramming by upregulating glycolysis and mitochondrial metabolism in macrophages. Altogether, PGAM5 signaling is a linker between alterations in Drp1-mediated mitochondrial dynamics and inflammatory responses in macrophages and may be a target for the treatment of inflammatory diseases.

Keywords:  inflammatory response; innate immunity; macrophages; metabolism; mitochondria; signaling/signaling pathways

DOI:  https://doi.org/10.3389/fimmu.2023.1243548
bioRxiv. 2023 Sep 13. pii: 2023.09.13.557496. [Epub ahead of print]

Tissue-Specific Dependence of Th1 Cells on the Amino Acid Transporter SLC38A1 in Inflammation.

Ayaka Sugiura, Katherine L Beier, Channing Chi, Darren R Heintzman, Xiang Ye, Melissa M Wolf, Andrew R Patterson, Jacqueline-Yvonne Cephus, Hanna S Hong, Costas A Lyssiotis, Dawn C Newcomb, Jeffrey C Rathmell.

Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4 + T cell subset requirements for specific AA remains uncertain. Here we tested CD4 + T cell AA demands with in vitro and multiple in vivo CRISPR screens and identify subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion over time in vitro and in vivo lung inflammation, SLC38A1 was critical for Th1 but not Th17 cell-driven Experimental Autoimmune Encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing intracellular glutamine and disrupting hexosamine biosynthesis and redox regulation. Similarly, pharmacological inhibition of SLC38 transporters delayed EAE but did not affect lung inflammation. Subset- and tissue-specific dependencies of CD4 + T cells on AA transporters may guide selective immunotherapies.HIGHLIGHTS: T cells dynamically regulate glutamine amino acid transporters when activatedSLC38A1 supports Th1 cell mTORC1 and proliferation by redox and hexosamine pathwaysTargeting SLC38A1 does not affect lung inflammation but delays IBD and EAENutrient transporter needs of T cell subsets vary based on disease and tissue site.

DOI: https://doi.org/10.1101/2023.09.13.557496
Nat Commun. 2023 Sep 26. 14(1): 5989

Orai inhibition modulates pulmonary ILC2 metabolism and alleviates airway hyperreactivity in murine and humanized models.

Emily Howard, Benjamin P Hurrell, Doumet Georges Helou, Pedram Shafiei-Jahani, Spyridon Hasiakos, Jacob Painter, Sonal Srikanth, Yousang Gwack, Omid Akbari.

Ca2+ entry via Ca2+ release-activated Ca2+ (CRAC) channels is a predominant mechanism of intracellular Ca2+ elevation in immune cells. Here we show the immunoregulatory role of CRAC channel components Orai1 and Orai2 in Group 2 innate lymphoid cells (ILC2s), that play crucial roles in the induction of type 2 inflammation. We find that blocking or genetic ablation of Orai1 and Orai2 downregulates ILC2 effector function and cytokine production, consequently ameliorating the development of ILC2-mediated airway inflammation in multiple murine models. Mechanistically, ILC2 metabolic and mitochondrial homeostasis are inhibited and lead to the upregulation of reactive oxygen species production. We confirm our findings in human ILC2s, as blocking Orai1 and Orai2 prevents the development of airway hyperreactivity in humanized mice. Our findings have a broad impact on the basic understanding of Ca2+ signaling in ILC2 biology, providing potential insights into the development of therapies for the treatment of allergic and atopic inflammatory diseases.

DOI: https://doi.org/10.1038/s41467-023-41065-4
J Immunol. 2023 Sep 27. pii: ji2300293. [Epub ahead of print]

Oxidized Low-Density Lipoprotein Accumulation Suppresses Glycolysis and Attenuates the Macrophage Inflammatory Response by Diverting Transcription from the HIF-1α to the Nrf2 Pathway.

Kenneth K Y Ting, Pei Yu, Riley Dow, Eric Floro, Hisham Ibrahim, Corey A Scipione, Sharon J Hyduk, Chanele K Polenz, Olga Zaslaver, Peer W F Karmaus, Michael B Fessler, Hannes L Röst, Michael Ohh, Sue Tsai, Daniel A Winer, Minna Woo, Jonathan Rocheleau, Jenny Jongstra-Bilen, Myron I Cybulsky.

Lipid accumulation in macrophages (Mφs) is a hallmark of atherosclerosis, yet how lipid accumulation affects inflammatory responses through rewiring of Mφ metabolism is poorly understood. We modeled lipid accumulation in cultured wild-type mouse thioglycolate-elicited peritoneal Mφs and bone marrow-derived Mφs with conditional (Lyz2-Cre) or complete genetic deficiency of Vhl, Hif1a, Nos2, and Nfe2l2. Transfection studies employed RAW264.7 cells. Mφs were cultured for 24 h with oxidized low-density lipoprotein (oxLDL) or cholesterol and then were stimulated with LPS. Transcriptomics revealed that oxLDL accumulation in Mφs downregulated inflammatory, hypoxia, and cholesterol metabolism pathways, whereas the antioxidant pathway, fatty acid oxidation, and ABC family proteins were upregulated. Metabolomics and extracellular metabolic flux assays showed that oxLDL accumulation suppressed LPS-induced glycolysis. Intracellular lipid accumulation in Mφs impaired LPS-induced inflammation by reducing both hypoxia-inducible factor 1-α (HIF-1α) stability and transactivation capacity; thus, the phenotype was not rescued in Vhl-/- Mφs. Intracellular lipid accumulation in Mφs also enhanced LPS-induced NF erythroid 2-related factor 2 (Nrf2)-mediated antioxidative defense that destabilizes HIF-1α, and Nrf2-deficient Mφs resisted the inhibitory effects of lipid accumulation on glycolysis and inflammatory gene expression. Furthermore, oxLDL shifted NADPH consumption from HIF-1α- to Nrf2-regulated apoenzymes. Thus, we postulate that repurposing NADPH consumption from HIF-1α to Nrf2 transcriptional pathways is critical in modulating inflammatory responses in Mφs with accumulated intracellular lipid. The relevance of our in vitro models was established by comparative transcriptomic analyses, which revealed that Mφs cultured with oxLDL and stimulated with LPS shared similar inflammatory and metabolic profiles with foamy Mφs derived from the atherosclerotic mouse and human aorta.

DOI: https://doi.org/10.4049/jimmunol.2300293
J Neurochem. 2023 Sep 27.

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury.

Nathan R Strogulski, Luis V Portela, Brian M Polster, David J Loane.

  Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain-infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro- and anti-inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro-inflammatory activation is associated with decreased mitochondrial respiration, whereas anti-inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post-traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non-resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post-traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.

Keywords:  metabolism; microglia; mitochondria; neuroimmunology; traumatic brain injury

DOI:  https://doi.org/10.1111/jnc.15959
mBio. 2023 Sep 29. e0086323

Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections.

Sidney Lane, Tristan L A White, Erin E Walsh, Richard T Cattley, Rachel Cumberland, William F Hawse, Greg M Delgoffe, Stephen F Badylak, Jennifer M Bomberger.

  Extracellular vesicles (EVs) are produced by most known cell types as a form of intercellular communication to influence the physiological function of neighboring cells. During respiratory viral-bacterial coinfection, the preceding antiviral response can lead to an impaired antibacterial response, driven by miscommunication between cells responding to viruses and cells responding to bacteria. Previous studies have shown that antiviral signaling can influence EV cargo and promote antiviral defense in the recipient cell; however, how antiviral EVs may influence host defense against coinfecting microorganisms, specifically bacteria, is not known. Herein, we demonstrated that EVs released from the respiratory epithelium during antiviral signaling alter macrophage inflammatory signaling, induce anti-inflammatory metabolic reprogramming, and impair antibacterial activity against Staphylococcus aureus, a common coinfecting bacterial pathogen. Further proteomic analysis revealed that antiviral EVs are preferentially loaded with pyruvate kinase M2 (PKM2), a metabolic enzyme with immunomodulatory effects, and treatment with antiviral EVs leads to increased PKM2 in macrophages. Moreover, we showed that antiviral EV-treated macrophages displayed enhanced oxidative phosphorylation, a metabolic profile consistent with impaired S. aureus clearance, and that this metabolic state is phenocopied in macrophages treated with a PKM2 activator. Taken together, our findings identify EVs as a component of the epithelial antiviral response that contributes to impaired bacterial clearance through epithelial-macrophage crosstalk and suggest a role for EVs in driving disease progression during respiratory coinfection. IMPORTANCE Miscommunication of antiviral and antibacterial immune signals drives worsened morbidity and mortality during respiratory viral-bacterial coinfections. Extracellular vesicles (EVs) are a form of intercellular communication with broad implications during infection, and here we show that epithelium-derived EVs released during the antiviral response impair the antibacterial activity of macrophages, an innate immune cell crucial for bacterial control in the airway. Macrophages exposed to antiviral EVs display reduced clearance of Staphylococcus aureus as well as altered inflammatory signaling and anti-inflammatory metabolic reprogramming, thus revealing EVs as a source of dysregulated epithelium-macrophage crosstalk during coinfection. As effective epithelium-macrophage communication is critical in mounting an appropriate immune response, this novel observation of epithelium-macrophage crosstalk shaping macrophage metabolism and antimicrobial function provides exciting new insight and improves our understanding of immune dysfunction during respiratory coinfections.

Keywords:  antiviral signaling; extracellular vesicles; host-pathogen interactions; macrophage; respiratory epithelium

DOI:  https://doi.org/10.1128/mbio.00863-23
Neurochem Int. 2023 Sep 23. pii: S0197-0186(23)00142-0. [Epub ahead of print] 105614

The immunometabolic reprogramming of microglia in Alzheimer's disease.

Hongli Chen, Zichen Guo, Yaxuan Sun, Xueling Dai.

  Alzheimer's disease (AD) is an age-related neurodegenerative disorder (NDD). In the central nervous system (CNS), immune cells like microglia could reprogram intracellular metabolism to alter or exert cellular immune functions in response to environmental stimuli. In AD, microglia could be activated and differentiated into pro-inflammatory or anti-inflammatory phenotypes, and these differences in cellular phenotypes resulted in variance in cellular energy metabolism. Considering the enormous energy requirement of microglia for immune functions, the changes in mitochondria-centered energy metabolism and substrates of microglia are crucial for the cellular regulation of immune responses. Here we reviewed the mechanisms of microglial metabolic reprogramming by analyzing their flexible metabolic patterns and changes that occurred in their metabolism during the development of AD. Further, we summarized the role of drugs in modulating immunometabolic reprogramming to prevent neuroinflammation, which may shed light on a new research direction for AD treatment.

Keywords:  Alzheimer's disease; Immunometabolism; Microglia; Neuroinflammation; Reprogramming

DOI:  https://doi.org/10.1016/j.neuint.2023.105614
Cancer Immunol Res. 2023 Sep 27.

Antigen priming induces functional reprogramming in iNKT cells via metabolic and epigenetic regulation: An insight into iNKT cell-based anti-tumor immunotherapy.

Huimin Zhang, Sanwei Chen, Yuwei Zhang, Chenxi Tian, Jun Pan, Yu Wang, Shiyu Bai, Qielan Wu, Miya Su, Di Xie, Sicheng Fu, Shuhang Li, Jing Zhang, Yusheng Chen, Shasha Zhu, Yeben Qian, Li Bai.

Dysfunction of intratumoral invariant natural killer T (iNKT) cells hinders their anti-tumor efficacy, but the underlying mechanisms and the relationship with endogenous antigen priming remain to be explored. Here, we report that antigen priming leads to metabolic reprogramming and epigenetic remodeling, which causes functional reprogramming in iNKT cells, characterized by limited cytokine responses upon restimulation but constitutive high cytotoxicity. Mechanistically, impaired oxidative phosphorylation (OXPHOS) in antigen-primed iNKT cells inhibited TCR signaling, as well as elevation of glycolysis, upon restimulation via reducing mTORC1 activation, and thus led to impaired cytokine production. However, the metabolic reprogramming in antigen-primed iNKT cells was uncoupled with their enhanced cytotoxicity; instead, epigenetic remodeling explained their high expression of granzymes. Notably, intratumoral iNKT cells shared similar metabolic reprogramming and functional reprogramming with antigen-primed iNKT cells due to endogenous antigen priming in tumors, and thus recovery of OXPHOS in intratumoral iNKT cells by ZLN005 successfully enhanced their anti-tumor responses. Our study deciphers the influences of antigen priming-induced metabolic reprogramming and epigenetic remodeling on functionality of intratumoral iNKT cells, and proposes a way to enhance efficacy of iNKT cell-based anti-tumor immunotherapy by targeting cellular metabolism.

DOI: https://doi.org/10.1158/2326-6066.CIR-23-0448
Trends Pharmacol Sci. 2023 Sep 26. pii: S0165-6147(23)00179-7. [Epub ahead of print]

Metabolic adaptation of NK cell activity and behavior in tumors: challenges and therapeutic opportunities.

Shambhavi Borde, Sandro Matosevic.

  The adaptation of natural killer (NK) cells to conditions in the microenvironment of tumors is deeply affected by their metabolic activity, itself a result of nutrient availability and the metabolism of the cancer cells themselves. Elevated rates of glycolysis and lipid metabolism in cancers not only lead to the accumulation of immunosuppressive byproducts but also contribute to an environment of elevated concentrations of extracellular metabolites. This results in altered NK cell bioenergetics through changes in transcriptional and translational profiles, ultimately affecting their pharmacology and impairing NK cell responses. However, understanding the metabolic processes that drive alterations in immunological signaling on NK cells remains both difficult and vastly underexplored. We discuss the varied and complex drivers of NK cell metabolism in homeostasis and the tumor microenvironment (TME), challenges associated with their targetability, and unexplored therapeutic opportunities.

Keywords:  NK cells; cancer immunotherapy; cancer metabolism; immunometabolism; tumor bioenergetics

DOI:  https://doi.org/10.1016/j.tips.2023.08.009
iScience. 2023 Sep 15. 26(9): 107593

Leishmania major centrin knock-out parasites reprogram tryptophan metabolism to induce a pro-inflammatory response.

Timur Oljuskin, Nazli Azodi, Greta Volpedo, Parna Bhattacharya, Hannah L Markle, Shinjiro Hamano, Greg Matlashewski, Abhay R Satoskar, Sreenivas Gannavaram, Hira L Nakhasi.

  Leishmaniasis is a parasitic disease that is prevalent in 90 countries, and yet no licensed human vaccine exists against it. Toward control of leishmaniasis, we have developed Leishmania major centrin gene deletion mutant strains (LmCen-/-) as a live attenuated vaccine, which induces a strong IFN-γ-mediated protection to the host. However, the immune mechanisms of such protection remain to be understood. Metabolomic reprogramming of the host cells following Leishmania infection has been shown to play a critical role in pathogenicity and shaping the immune response following infection. Here, we applied untargeted mass spectrometric analysis to study the metabolic changes induced by infection with LmCen-/- and compared those with virulent L. major parasite infection to identify the immune mechanism of protection. Our data show that immunization with LmCen-/- parasites, in contrast to virulent L. major infection promotes a pro-inflammatory response by utilizing tryptophan to produce melatonin and downregulate anti-inflammatory kynurenine-AhR and FICZ-AhR signaling.

Keywords:  Immunology; Metabolomics; Parasitology

DOI:  https://doi.org/10.1016/j.isci.2023.107593
Int J Mol Sci. 2023 Sep 16. pii: 14173. [Epub ahead of print]24(18):

New Insights in Immunometabolism in Neonatal Monocytes and Macrophages in Health and Disease.

Renske de Jong, Klaus Tenbrock, Kim Ohl.

  It is well established that the neonatal immune system is different from the adult immune system. A major task of the neonatal immune system is to bridge the achievement of tolerance towards harmless antigens and commensal bacteria while providing protection against pathogens. This is highly important because neonates are immunologically challenged directly after birth by a rigorous change from a semi-allogeneic sterile environment into a world rich with microbes. A so called disease tolerogenic state is typical for neonates and is anticipated to prevent immunopathological damage potentially at the cost of uncontrolled pathogen proliferation. As a consequence, neonates are more susceptible than adults to life-threatening infections. At the basis of a well-functioning immune response, both for adults and neonates, innate immune cells such as monocytes and monocyte-derived macrophages play an essential role. A well-responsive monocyte will alter its cellular metabolism to subsequently induce certain immune effector function, a process which is called immunometabolism. Immunometabolism has received extensive attention in the last decade; however, it has not been broadly studied in neonates. This review focuses on carbohydrate metabolism in monocytes and macrophages in neonates. We will exhibit pathways involving glycolysis, the tricarboxylic acid (TCA) cycle and oxidative phosphorylation and their role in shaping neonates' immune systems to a favorable tolerogenic state. More insight into these pathways will elucidate potential treatments targets in life-threatening conditions including neonatal sepsis or expose potential targets which can be used to induce tolerance in conditions where tolerance is harmfully impaired such as in autoimmune diseases.

Keywords:  bacterial; commensals; neonatal infection; neonatal tolerance

DOI:  https://doi.org/10.3390/ijms241814173
J Neuroinflammation. 2023 Sep 27. 20(1): 217

Glycolytic shift during West Nile virus infection provides new therapeutic opportunities.

Patricia Mingo-Casas, Ana-Belén Blázquez, Marta Gómez de Cedrón, Ana San-Félix, Susana Molina, Estela Escribano-Romero, Eva Calvo-Pinilla, Nereida Jiménez de Oya, Ana Ramírez de Molina, Juan-Carlos Saiz, María-Jesús Pérez-Pérez, Miguel A Martín-Acebes.

  BACKGROUND: Viral rewiring of host bioenergetics and immunometabolism may provide novel targets for therapeutic interventions against viral infections. Here, we have explored the effect on bioenergetics during the infection with the mosquito-borne flavivirus West Nile virus (WNV), a medically relevant neurotropic pathogen causing outbreaks of meningitis and encephalitis worldwide.RESULTS: A systematic literature search and meta-analysis pointed to a misbalance of glucose homeostasis in the central nervous system of WNV patients. Real-time bioenergetic analyses confirmed upregulation of aerobic glycolysis and a reduction of mitochondrial oxidative phosphorylation during viral replication in cultured cells. Transcriptomics analyses in neural tissues from experimentally infected mice unveiled a glycolytic shift including the upregulation of hexokinases 2 and 3 (Hk2 and Hk3) and pyruvate dehydrogenase kinase 4 (Pdk4). Treatment of infected mice with the Hk inhibitor, 2-deoxy-D-glucose, or the Pdk4 inhibitor, dichloroacetate, alleviated WNV-induced neuroinflammation.
CONCLUSIONS: These results highlight the importance of host energetic metabolism and specifically glycolysis in WNV infection in vivo. This study provides proof of concept for the druggability of the glycolytic pathway for the future development of therapies to combat WNV pathology.

Keywords:  Glycolysis; Immunometabolism; Neuroinflammation; West Nile virus

DOI:  https://doi.org/10.1186/s12974-023-02899-3
Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01183-X. [Epub ahead of print]42(10): 113171

Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis.

Yang Zhao, Yuhao Liu, Guizhen Zhao, Haocheng Lu, Yaozhong Liu, Chao Xue, Ziyi Chang, Hongyu Liu, Yongjie Deng, Wenying Liang, Huilun Wang, Oren Rom, Minerva T Garcia-Barrio, Tianqing Zhu, Yanhong Guo, Lin Chang, Jiandie Lin, Y Eugene Chen, Jifeng Zhang.

  Atherosclerosis, a leading health concern, stems from the dynamic involvement of immune cells in vascular plaques. Despite its significance, the interplay between chromatin remodeling and transcriptional regulation in plaque macrophages is understudied. We discovered the reduced expression of Baf60a, a component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, in macrophages from advanced plaques. Myeloid-specific Baf60a deletion compromised mitochondrial integrity and heightened adhesion, apoptosis, and plaque development. BAF60a preserves mitochondrial energy homeostasis under pro-atherogenic stimuli by retaining nuclear respiratory factor 1 (NRF1) accessibility at critical genes. Overexpression of BAF60a rescued mitochondrial dysfunction in an NRF1-dependent manner. This study illuminates the BAF60a-NRF1 axis as a mitochondrial function modulator in atherosclerosis, proposing the rejuvenation of perturbed chromatin remodeling machinery as a potential therapeutic target.

Keywords:  CP: Metabolism; CP: Molecular biology; SWI/SNF; atherosclerosis; chromatin remodeling; macrophage; mitochondria

DOI:  https://doi.org/10.1016/j.celrep.2023.113171
iScience. 2023 Sep 15. 26(9): 107594

Leishmania mexicana centrin knockout parasites promote M1-polarizing metabolic changes.

Greta Volpedo, Thalia Pacheco-Fernandez, Timur Oljuskin, Hannah L Markle, Nazli Azodi, Shinjiro Hamano, Greg Matlashewski, Sreenivas Gannavaram, Hira L Nakhasi, Abhay R Satoskar.

  Leishmaniasis is a tropical disease prevalent in 90 countries. Presently, there is no approved vaccine for human use. We developed a live attenuated L. mexicana Cen-/-(LmexCen-/-) strain as a vaccine candidate that showed excellent efficacy, characterized by reduced Th2 and enhanced Th1 responses in C57BL/6 and BALB/c mice, respectively, compared to wild-type L. mexicana (LmexWT) infection. Toward understanding the immune mechanisms of protection, we applied untargeted mass spectrometric analysis to LmexCen-/- and LmexWT infections. Data showed enrichment of the pentose phosphate pathway (PPP) in ears immunized with LmexCen-/-versus naive and LmexWT infection. PPP promotes M1 polarization in macrophages, suggesting a switch to a pro-inflammatory phenotype following LmexCen-/- inoculation. Accordingly, PPP inhibition in macrophages infected with LmexCen-/- reduced the production of nitric oxide and interleukin (IL)-1β, hallmarks of classical activation. Overall, our study revealed the immune regulatory mechanisms that may be critical for the induction of protective immunity.

Keywords:  Immunology; Metabolomics; Parasitology

DOI:  https://doi.org/10.1016/j.isci.2023.107594
Inflammation. 2023 Sep 27.

Anti-Necroptotic Effects of Itaconate and its Derivatives.

Si-Tao Ni, Qing Li, Ying Chen, Fu-Li Shi, Tak-Sui Wong, Li-Sha Yuan, Rong Xu, Ying-Qing Gan, Na Lu, Ya-Ping Li, Zhi-Ya Zhou, Li-Hui Xu, Xian-Hui He, Bo Hu, Dong-Yun Ouyang.

  Itaconate is an unsaturated dicarboxylic acid that is derived from the decarboxylation of the Krebs cycle intermediate cis-aconitate and has been shown to exhibit anti-inflammatory and anti-bacterial/viral properties. But the mechanisms underlying itaconate's anti-inflammatory activities are not fully understood. Necroptosis, a lytic form of regulated cell death (RCD), is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) signaling. It has been involved in the pathogenesis of organ injury in many inflammatory diseases. In this study, we aimed to explore whether itaconate and its derivatives can inhibit necroptosis in murine macrophages, a mouse MPC-5 cell line and a human HT-29 cell line in response to different necroptotic activators. Our results showed that itaconate and its derivatives dose-dependently inhibited necroptosis, among which dimethyl itaconate (DMI) was the most effective one. Mechanistically, itaconate and its derivatives inhibited necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling and the oligomerization of MLKL. Furthermore, DMI promoted the nuclear translocation of Nrf2 that is a critical regulator of intracellular redox homeostasis, and reduced the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide (mtROS) that were induced by necroptotic activators. Consistently, DMI prevented the loss of mitochondrial membrane potential induced by the necroptotic activators. In addition, DMI mitigated caerulein-induced acute pancreatitis in mice accompanied by reduced activation of the necroptotic signaling in vivo. Collectively, our study demonstrates that itaconate and its derivatives can inhibit necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling, highlighting their potential applications for treating necroptosis-associated diseases.

Keywords:  Dimethyl itaconate; Itaconate; MLKL; Necroptosis; RIPK1; RIPK3

DOI:  https://doi.org/10.1007/s10753-023-01909-z
Hepatol Commun. 2023 Oct 01. pii: e0236. [Epub ahead of print]7(10):

Exercise changes the intrahepatic immune cell profile and inhibits the progression of nonalcoholic steatohepatitis in a mouse model.

Yuriko Tsutsui, Taizo Mori, Sachiyo Yoshio, Miku Sato, Toshihiro Sakata, Yuichi Yoshida, Hironari Kawai, Shiori Yoshikawa, Taiji Yamazoe, Michitaka Matsuda, Eiji Kakazu, Yosuke Osawa, Chinatsu Oyama, Miwa Tamura-Nakano, Takumi Kawaguchi, Tomoharu Yoshizumi, Tatsuya Kanto.

BACKGROUND: NASH is an increasingly common cause of chronic liver disease and can progress to cirrhosis and HCC. Although exercise suppresses inflammation during acute hepatitis, its impact on the progression of chronic liver disease remains unclear. Here, we investigated the effects of exercise on disease progression and intrahepatic immune cell composition in a mouse model of NASH.METHOD: Mice were assigned to 4 groups: 2 control groups (normal diet) and 2 NASH groups (western diet and low-dose carbon tetrachloride injection). One of each group remained sedentary and one was exercised on a treadmill for 12 weeks (60 min/d, 5 times/wk). All mice were then analyzed for liver histomorphology, steatosis, inflammation, and fibrosis; liver, adipose tissue, and skeletal muscle expression of genes related to metabolism and inflammation; and intrahepatic immune cell composition.
RESULT: Compared with the normal diet mice, NASH mice exhibited enhanced liver steatosis, inflammation, and fibrosis; upregulated expression of liver lipogenesis-related and inflammation-related genes; and increased frequencies of intrahepatic F4/80int CD11bhi bone marrow-derived macrophages and programmed death receptor-1 (PD-1)+ CD8+ T cells. Expression of inflammatory cytokines and the frequencies of bone marrow-derived macrophages and PD-1+ CD8+ T cells correlated positively with liver steatosis, inflammation, and fibrosis. Exercise was shown to reduce NASH-induced hepatic steatosis, liver inflammation, and fibrosis; induce alterations in metabolism-related genes and inflammatory cytokines in the liver; and suppress accumulation of liver bone marrow-derived macrophages and PD-1+ CD8+ T cells. In addition, we showed that exercise induced increased expression of IL-15 in muscle and its deficiency exacerbated the pathology of NASH.
CONCLUSIONS: Exercise alters the intrahepatic immune cell profile and protects against disease progression in a mouse model of NASH.

DOI: https://doi.org/10.1097/HC9.0000000000000236
Front Immunol. 2023 ;14 1238774

Identification of potential hub genes linked to immune and metabolic alterations in postoperative systemic inflammatory dysregulation.

Silu Cao, Jinxuan Tang, Miaomiao Fei, Qi Jing, Fanbing Meng, Meixian Zhang, Qidong Liu, Hui Zhang, Cheng Li.

  Background: Postoperative systemic inflammatory dysregulation (PSID) is characterised by strongly interlinked immune and metabolic abnormalities. However, the hub genes responsible for the interconnections between these two systemic alterations remain to be identified.Methods: We analysed differentially expressed genes (DEGs) of individual peripheral blood nucleated cells in patients with PSID (n = 21, CRP > 250 mg/L) and control patients (n = 25, CRP < 75 mg/L) following major abdominal surgery, along with their biological functions. Correlation analyses were conducted to explore the interconnections of immune-related DEGs (irDEGs) and metabolism-related DEGs (mrDEGs). Two methods were used to screen hub genes for irDEGs and mrDEGs: we screened for hub genes among DEGs via 12 algorithms using CytoHubba in Cytoscape, and also screened for hub immune-related and metabolic-related genes using weighted gene co-expression network analysis. The hub genes selected were involved in the interaction between changes in immunity and metabolism in PSID. Finally, we validated our results in mice with PSID to confirm the findings.
Results: We identified 512 upregulated and 254 downregulated DEGs in patients with PSID compared with controls. Gene enrichment analysis revealed that DEGs were significantly associated with immune- and metabolism-related biological processes and pathways. Correlation analyses revealed a close association between irDEGs and mrDEGs. Fourteen unique hub genes were identified via 12 screening algorithms using CytoHubba in Cytoscape and via weighted gene co-expression network analysis. Among these, CD28, CD40LG, MAPK14, and S100A12 were identified as hub genes among both immune- and metabolism-related genes; these genes play a critical role in the interaction between alterations in immunity and metabolism in PSID. The experimental results also showed that the expression of these genes was significantly altered in PSID mice.
Conclusion: This study identified hub genes associated with immune and metabolic alterations in patients with PSID and hub genes that link these alterations. These findings provide novel insights into the mechanisms underlying immune and metabolic interactions and new targets for clinical treatment can be proposed on this basis.

Keywords:  C-reactive protein; hub genes; metabolism; postoperative systemic inflammatory dysregulation; surgery

DOI:  https://doi.org/10.3389/fimmu.2023.1238774
Cell Rep. 2023 Sep 27. pii: S2211-1247(23)01152-X. [Epub ahead of print]42(10): 113140

Low dietary fiber intake impairs small intestinal Th17 and intraepithelial T cell development over generations.

Charlotte J Royer, Naomi Rodriguez-Marino, Madelyn D Yaceczko, Dormarie E Rivera-Rodriguez, Thomas R Ziegler, Luisa Cervantes-Barragan.

  Dietary fiber strongly impacts the microbiota. Here, we show that a low-fiber diet changes the small intestinal (SI) microbiota and impairs SI Th17, TCRαβ+CD8αβ+ and TCRαβ+CD8αα+ intraepithelial T cell development. We restore T cell development with dietary fiber supplementation, but this defect becomes persistent over generations with constant low-fiber diets. Offspring of low-fiber diet-fed mice have reduced SI T cells even after receiving a fiber-rich diet due to loss of bacteria important for T cell development. In these mice, only a microbiota transplant from a fiber-rich diet-fed mouse and a fiber-rich diet can restore T cell development. Low-fiber diets reduce segmented filamentous bacteria (SFB) abundance, impairing its vertical transmission. SFB colonization and a fiber-rich diet partially restore T cell development. Finally, we observe that low-fiber diet-induced T cell defects render mice more susceptible to Citrobacter rodentium infection. Together, these results demonstrate the importance of fiber to microbiota vertical transmission and host immune system development.

Keywords:  CD8αβ(+) IEL; CP: Immunology; CP: Microbiology; IEL T cells; Th17; dietary fiber; interleukin 17; intraepithelial; microbiota; segmented filamentous bacteria

DOI:  https://doi.org/10.1016/j.celrep.2023.113140
Front Immunol. 2023 ;14 1212745

Mild to moderate post-COVID-19 alters markers of lymphocyte activation, exhaustion, and immunometabolic responses that can be partially associated by physical activity level- an observational sub-analysis fit- COVID study.

Bruna Spolador de Alencar Silva, Telmo Pereira, Luciele Guerra Minuzzi, Camila Souza Padilha, Caique Figueiredo, Tiago Olean-Oliveira, Ivete Vera Medeiros Dos Santos, Ana Elisa von Ah Morano, Osmar Marchioto Júnior, José Procópio Jabur Ribeiro, Vanessa Ribeiro Dos Santos, Marília Seelaender, Alexandre Abílio Teixeira, Ronaldo Vagner T Dos Santos, Valdir de Aquino Lemos, Ana Paula Coelho Figueira Freire, Gilson Pires Dorneles, Bruna Marmett, André Olean-Oliveira, Marcos F S Teixeira, Patrícia M Seraphim, Armando Caseiro, Ricardo Aurino Pinho, Hashim Islam, Jonathan Peter Little, Karsten Krüger, José César Rosa-Neto, Manuel-João Coelho-E-Silva, Fábio Santos Lira.

  Aim: This study aimed to evaluate if physical activity is associated with systemic and cellular immunometabolic responses, in young adults after mild-to-moderate COVID-19 infection.Methods: Mild- to- moderate post-COVID-19 patients (70.50 ± 43.10 days of diagnosis; age: 29.4 (21.9- 34.9) years; BMI: 25.5 ± 4.3 kg m2 n = 20) and healthy age-matched controls (age: 29.3 (21.2 - 32.6) years; BMI: 25.4 ± 4.7 kg m2; n = 20) were evaluated. Physical activity levels (PAL), body composition, dietary habits, muscular and pulmonary function, mental health, sleep quality, metabolic parameters, immune phenotypic characterization, stimulated whole blood and PBMC culture (cytokine production), mRNA, and mitochondrial respiration in PBMCs were evaluated.
Results: The post-COVID-19 group exhibited lower levels of moderate to vigorous physical activity (MVPA) (p = 0.038); therefore, all study comparisons were performed with adjustment for MVPA. Post-COVID-19 impacted the pulmonary function (FEV1, FEV1%pred, FVC, and FVC %pred) compared with the control (p adjusted by MVPA (p adj) <0.05). Post-COVID-19 exhibited lower levels of serum IL-6 (p adj <0.01), whereas it showed higher serum IL-10, triglyceride, leptin, IgG, ACE activity, TNFRSF1A, and PGE2 (p adj <0.05) levels compared with controls. Post-COVID-19 presented a lower percentage of Treg cells (p adj = 0.03) and altered markers of lymphocyte activation and exhaustion (lower CD28 expression in CD8+ T cells (p adj = 0.014), whereas CD4+T cells showed higher PD1 expression (p adj = 0.037)) compared with the control group. Finally, post- COVID-19 presented an increased LPS-stimulated whole- blood IL-10 concentration (p adj <0.01). When exploring mitochondrial respiration and gene expression in PBMCs, we observed a higher LEAK state value (p adj <0.01), lower OXPHOS activity (complex I) (p adj = 0.04), and expression of the Rev-Erb-α clock mRNA after LPS stimulation in the post-COVID-19 patients than in the control (p adj <0.01). Mainly, PAL was associated with changes in IL-10, triglyceride, and leptin levels in the plasma of post-COVID-19 patients. PAL was also associated with modulation of the peripheral frequency of Treg cells and the expression of PD-1 in CD8+ T cells, although it abrogated the statistical effect in the analysis of TNF-α and IL-6 production by LPS- and PMA-stimulated PBMC of post-COVID-19 patients.
Conclusion: Young adults after mild-to-moderate SARS-CoV-2 infection appeared to have lower physical activity levels, which can be associated with clinical and immunometabolic responses in a complex manner.

Keywords:  SARS-CoV-2; immune response; inflammation; metabolism; physical activity; post-acute COVID-19 syndrome

DOI:  https://doi.org/10.3389/fimmu.2023.1212745
Int J Neurosci. 2023 Sep 25. 1-16

IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice.

Jian Lu, Ye Zhang, Qian Hao, Hongmei Zhou, Youming Zong.

  Postoperative cognitive dysfunction (POCD) is a common postoperative complication, especially in elderly patients. It extends hospital stay, increases the mortality rate and are heavy burdens to the family and society. Accumulating research has indicated that overactivation of pyrin domain-containing protein 3 (NLRP3) inflammasomes is related to POCD. The NLRP3 inflammasome plays a critical role in activating pro-inflammatory cytokines. According to existing studies, indoleamine 2,3-dioxygenase (IDO) is potently up-regulated by inflammatory factors, tryptophan in brain is mainly catalyzed by IDO to kynurenine (KYN), IDO-Kynurenine metabolism may contribute to the development of depressive disorder and memory deficits. Hence, this study elucidated whether IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment in aged mice.POCD model was established in aged C57BL/6J mice by exploratory laparotomy under isoflurane anesthesia. Morris Water maze (MWM) was used to evaluate learning and memory abilities. We found that IDO and kynurenine aminotransferase-II (KAT-II) mRNA in hippocampus was up-regulated, and NLRP3, ASC, IL-1β and IDO overexpressed, KYN levels increased after anesthesia and surgery. Furthermore, we treated these mice with the NLRP3 inflammasome inhibitor (MCC950) to observe its effect on the expression of the NLRP3, ASC, IL-1β and IDO and KYN levels. We found that MCC950 reversed NLRP3, ASC, IL-1β and IDO overexpression, and the elevation of KYN levels, suggesting that IDO may be a downstream medium of the NLRP3 inflammasome. To clarify the role of IDO-Kynurenine pathway in postoperative cognitive impairment, we treated these mice with the IDO inhibitor 1-methyl-Ltryptophan (1-MT) to observe its effect on learning and memory abilities and the tryptophan (TRP), KYN and kynurenic acid (KYNA) levels. We found that 1-MT reduced the elevation of KYN and KYNA levels, and the reduction of TRP levels in the hippocampus, as well as improved learning and memory abilities in anesthesia/surgery mice. Finally, IDO overexpression led to the increase of KYNA levels in brain and cognitive impairment. Further study revealed that PF-04859989, a inhibitor of KAT-II (the major enzyme for brain KYNA synthesis) reduced brain KYNA levels, as well as restored the cognitive impairment. Together, these results reveal that IDO-Kynurenine pathway mediates NLRP3 inflammasome activation-induced postoperative cognitive impairment. IDO-Kynurenine pathway may be a novel target for the treatment of cognitive impairment induced by anesthesia and surgery in old patients.

Keywords:  3-dioxygenase; aged mice; indoleamine 2; inflammation; kynurenic acid; postoperative cognitive deficit

DOI:  https://doi.org/10.1080/00207454.2023.2262741
bioRxiv. 2023 Sep 16. pii: 2023.09.13.557599. [Epub ahead of print]

Plasma cell differentiation, antibody quality, and initial germinal center B cell population depend on glucose influx rate.

Shawna K Brookens, Sung Hoon Cho, Yeeun Paik, Kaylor Meyer, Ariel L Raybuck, Chloe Park, Dalton L Greenwood, Jeffrey C Rathmell, Mark R Boothby.

Antibody secretion into sera, selection for higher affinity BCR, and the generation of higher Ab affinities are important elements of immune response optimization, and a core function of germinal center reactions. B cell proliferation requires nutrients to support the anabolism inherent in clonal expansion. Glucose usage by GC B cells has been reported to contribute little to their energy needs, with questions raised as to whether or not glucose uptake or glycolysis increases in GC B cells compared to their naïve precursors. Indeed, metabolism can be highly flexible, such that supply shortage along one pathway may be compensated by increased flux on others. We now show that elimination of the glucose transporter GLUT1 after establishment of a pre-immune B cell repertoire, even after initiation of the GC B cell gene expression program, decreased initial GC B cell population numbers, affinity maturation, and PC outputs. Glucose oxidation was heightened in GC B cells, but this hexose flowed more into the pentose phosphate pathway (PPP), whose activity was important in controlling reactive oxygen (ROS) and ASC production. In modeling how glucose usage by B cells promotes the Ab response, the control of ROS appeared insufficient. Surprisingly, the combination of galactose, which mitigated ROS, with provision of mannose - an efficient precursor to glycosylation - supported robust production of and normal Ab secretion by ASC under glucose-free conditions. Collectively, the findings indicate that GC depend on normal glucose influx, especially in PC production, but reveal an unexpected metabolic flexibility in hexose requirements.KEY POINTS: Glucose influx is critical for GC homeostasis, affinity maturation and the generation of Ab-secreting cells.Plasma cell development uses the Pentose Phosphate Pathway, and hexose sugars maintain redox homeostasis.PCs can develop and achieve robust Ab secretion in the absence of glucose using a combination of hexose alternatives.

DOI: https://doi.org/10.1101/2023.09.13.557599
Immun Inflamm Dis. 2023 Sep;11(9): e1002

Mitochondrial dynamics modulate the allergic inflammation in a murine model of allergic rhinitis.

Xu-Qing Chen, Long-Yun Zhou, Hua-An Ma, Ji-Yong Wu, Shu-Fen Liu, Yong-Jun Wu, Dao-Nan Yan.

  OBJECTIVE: Allergic rhinitis (AR) is a common allergic disorder, afflicting thousands of human beings. Aberrant mitochondrial dynamics are important pathological elements for various immune cell dysfunctions and allergic diseases. However, the connection between mitochondrial dynamics and AR remains poorly understood. This study aimed to determine whether mitochondrial dynamics influence the inflammatory response in AR.METHODS: In the present study, we established a murine model of AR by sensitization with ovalbumin (OVA). Then, we investigated the mitochondrial morphology in mice with AR by transmission electron microscopy and confocal fluorescence microscopy, and evaluated the role of Mdivi-1 (an inhibitor of mitochondrial fission) on allergic symptoms, inflammatory responses, allergic-related signals, and reactive oxygen species formation.
RESULTS: There was a notable enhancement in mitochondrial fragmentation in the nasal mucosa of mice following OVA stimulation, whereas Mdivi-1 prevented aberrant mitochondrial morphology. Indeed, Mdivi-1 alleviated the rubbing and sneezing responses in OVA-sensitized mice. Compared with vehicle-treated ones, mice treated with Mdivi-1 exhibited a reduction in interleukin (IL)-4, IL-5, and specific IgE levels in both serum and nasal lavage fluid, and shown an amelioration in inflammatory response of nasal mucosa. Meanwhile, Mdivi-1 treatment was associated with a suppression in JAK2 and STAT6 activation and reactive oxygen species generation, which act as important signaling for allergic response.
CONCLUSION: Our findings reveal mitochondrial dynamics modulate the allergic responses in AR. Mitochondrial dynamics may represent a promising target for the treatment of AR.

Keywords:  Mdivi-1; allergic inflammation; allergic rhinitis; mitochondrial dynamics

DOI:  https://doi.org/10.1002/iid3.1002
EMBO J. 2023 Sep 25. e112963

A tryptophan metabolite made by a gut microbiome eukaryote induces pro-inflammatory T cells.

Lukasz Wojciech, Chin Wen Png, Eileen Y Koh, Dorinda Yan Qin Kioh, Lei Deng, Ziteng Wang, Liang-Zhe Wu, Maryam Hamidinia, Desmond Wh Tung, Wei Zhang, Sven Pettersson, Eric Chun Yong Chan, Yongliang Zhang, Kevin Sw Tan, Nicholas Rj Gascoigne.

  The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely on the balance between regulators and responder intestinal CD4+ T cells. We found that ulcerative colitis-like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti-inflammatory Treg cells and simultaneous expansion of pro-inflammatory Th17 responders. These alterations in CD4+ T cells depended on the tryptophan metabolite indole-3-acetaldehyde (I3AA) produced by this single-cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFβ, concomitantly affecting recognition of self-flora antigens by conventional CD4+ T cells. Parasite-derived I3AA also induces over-exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co-inhibitor PD-1. We have thus identified a new mechanism dictating CD4+ fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.

Keywords:  aryl hydrocarbon receptor; colitis; microbiome; regulatory T cells; tryptophan metabolites

DOI:  https://doi.org/10.15252/embj.2022112963
Front Med (Lausanne). 2023 ;10 1265398

Role of sphingosine 1-phosphate (S1P) in sepsis-associated intestinal injury.

Gehui Sun, Bin Wang, Hongquan Zhu, Junming Ye, Xiaofeng Liu.

  Sphingosine-1-phosphate (S1P) is a widespread lipid signaling molecule that binds to five sphingosine-1-phosphate receptors (S1PRs) to regulate downstream signaling pathways. Sepsis can cause intestinal injury and intestinal injury can aggravate sepsis. Thus, intestinal injury and sepsis are mutually interdependent. S1P is more abundant in intestinal tissues as compared to other tissues, exerts anti-inflammatory effects, promotes immune cell trafficking, and protects the intestinal barrier. Despite the clinical importance of S1P in inflammation, with a very well-defined mechanism in inflammatory bowel disease, their role in sepsis-induced intestinal injury has been relatively unexplored. In addition to regulating lymphocyte exit, the S1P-S1PR pathway has been implicated in the gut microbiota, intestinal epithelial cells (IECs), and immune cells in the lamina propria. This review mainly elaborates on the physiological role of S1P in sepsis, focusing on intestinal injury. We introduce the generation and metabolism of S1P, emphasize the maintenance of intestinal barrier homeostasis in sepsis, and the protective effect of S1P in the intestine. We also review the link between sepsis-induced intestinal injury and S1P-S1PRs signaling, as well as the underlying mechanisms of action. Finally, we discuss how S1PRs affect intestinal function and become targets for future drug development to improve the translational capacity of preclinical studies to the clinic.

Keywords:  S1P; S1PRs; immune; intestinal epithelial barrier; sepsis; signaling

DOI:  https://doi.org/10.3389/fmed.2023.1265398
Front Immunol. 2023 ;14 1241531

Phenotypic and functional characteristics of murine CD11c+ B cells which is suppressed by metformin.

Ivan Ramirez De Oleo, Vera Kim, Yemil Atisha-Fregoso, Andrew J Shih, Kyungwoo Lee, Betty Diamond, Sun Jung Kim.

  Since the description of age-associated or autoimmune-associated B cells (ABCs), there has been a growing interest in the role of these cells in autoimmunity. ABCs are differently defined depending on the research group and are heterogenous subsets. Here, we sought to characterize ABCs in Sle1/2/3 triple congenic (TC) mice, which is a well accepted mouse model of lupus. Compared to follicular (FO) B cells, ABCs have many distinct functional properties, including antigen presentation. They express key costimulatory molecules for T cell activation and a distinct profile of cytokines. Moreover, they exhibit an increased capacity for antigen uptake. ABCs were also compared with germinal center (GC) B cells, which are antigen activated B cell population. There are several phenotypic similarities between ABCs and GC B cells, but GC B cells do not produce proinflammatory cytokines or take up antigen. While T cell proliferation and activation is induced by both FO B and ABCs in an antigen-dependent manner, ABCs induce stronger T cell receptor signaling in naïve CD4+ T cells and preferentially induce differentiation of T follicular helper (Tfh) cells. We found that ABCs exhibit a distinct transcriptomic profile which is focused on metabolism, cytokine signaling and antigen uptake and processing. ABCs exhibit an increase in both glycolysis and oxidative phosphorylation compared to FO B cells. Treatment of ABCs with metformin suppresses antigen presentation by decreasing antigen uptake, resulting in decreased Tfh differentiation. Taken together, these findings define a fundamental connection between metabolism and function within ABCs.

Keywords:  age-associated B cells (ABCs); autoimmune diseases; follicular T helper cells (Tfh); metabolism; mouse model; systemic lupus erythematosus (SLE)

DOI:  https://doi.org/10.3389/fimmu.2023.1241531