bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒01‒16
thirty-nine papers selected by
Dylan Ryan
University of Cambridge

  1. Int J Mol Sci. 2021 Dec 21. pii: 37. [Epub ahead of print]23(1):
      Energy sensors mTORC1 and AMPKα1 regulate T-cell metabolism and differentiation, while rapamycin (Rapa)-inhibition of mTORC1 (RIM) promotes T-cell memory. However, the underlying pathway and the role of AMPKα1 in Rapa-induced T-cell memory remain elusive. Using genetic and pharmaceutical tools, we demonstrate that Rapa promotes T-cell memory in mice in vivo post Listeria monocytogenesis rLmOVA infection and in vitro transition of effector T (TE) to memory T (TM) cells. IL-2- and IL-2+Rapa-stimulated T [IL-2/T and IL-2(Rapa+)/T] cells, when transferred into mice, differentiate into short-term IL-7R-CD62L-KLRG1+ TE and long-lived IL-7R+CD62L+KLRG1- TM cells, respectively. To assess the underlying pathways, we performed Western blotting, confocal microscopy and Seahorse-assay analyses using IL-2/T and IL-2(Rapa+)/T-cells. We determined that IL-2(Rapa+)/T-cells activate transcription FOXO1, TCF1 and Eomes and metabolic pAMPKα1(T172), pULK1(S555) and ATG7 molecules and promote mitochondrial biogenesis and fatty-acid oxidation (FAO). We found that rapamycin-treated AMPKα-deficient AMPKα1-KO IL-2(Rapa+)/TM cells up-regulate transcription factor HIF-1α and induce a metabolic switch from FAO to glycolysis. Interestingly, despite the rapamycin treatment, AMPKα-deficient TM cells lost their cell survival capacity. Taken together, our data indicate that rapamycin promotes T-cell memory via transcriptional FOXO1-TCF1-Eomes programs and AMPKα1-ULK1-ATG7 metabolic axis, and that AMPKα1 plays a critical role in RIM-induced T-cell memory.
    Keywords:  AMPKα1; FOXO1; S6K; T-cell memory; ULK1; autophagy; fatty acid oxidation; glycolysis; mTORC1; mitochondrial biogenesis; rapamycin
  2. Immunity. 2022 Jan 11. pii: S1074-7613(21)00548-3. [Epub ahead of print]55(1): 14-30
      Adaptive immune responses mediated by T cells and B cells are crucial for protective immunity against pathogens and tumors. Differentiation and function of immune cells require dynamic reprogramming of cellular metabolism. Metabolic inputs, pathways, and enzymes display remarkable flexibility and heterogeneity, especially in vivo. How metabolic plasticity and adaptation dictate functional specialization of immune cells is fundamental to our understanding and therapeutic modulation of the immune system. Extensive progress has been made in characterizing the effects of metabolic networks on immune cell fate and function in discrete microenvironments or immunological contexts. In this review, we summarize how rewiring of cellular metabolism determines the outcome of adaptive immunity in vivo, with a focus on how metabolites, nutrients, and driver genes in immunometabolism instruct cellular programming and immune responses during infection, inflammation, and cancer in mice and humans. Understanding context-dependent metabolic remodeling will manifest legitimate opportunities for therapeutic intervention of human disease.
  3. Clin Exp Immunol. 2021 Nov 27. pii: uxab021. [Epub ahead of print]
      Rheumatoid Arthritis is a chronic autoimmune disease characterised by neovascularisation, immune cell infiltration and synovial hyperplasia, which leads to degradation of articular cartilage and bone, and subsequent functional disability. Dysregulated angiogenesis, synovial hypoxia and immune cell infiltration results in a 'bioenergetic crisis' in the inflamed joint which further exacerbates synovial invasiveness. Several studies have examined this vicious cycle between metabolism, immunity and inflammation and the role metabolites play in these interactions. To add to this complexity the inflamed synovium is a multicellular tissue with many cellular subsets having different metabolic requirements. Metabolites can shape the inflammatory phenotype of immune cell subsets during disease and act as central signaling hubs. In the RA joint the increased energy demand of stromal and immune cells leads to the accumulation of metabolites such as lactate, citrate, and succinate as well as adipocytokines which can regulate downstream signalling pathways. Transcription factors such as HIF1ɑ and mTOR can act as metabolic sensors to activate synovial cells and drive pro-inflammatory effector function, thus perpetuating chronic inflammation further. These metabolic intermediates may be potential therapeutic targets and so understanding the complex interplay between metabolites and synovial cells in RA may allow for identification of novel therapeutic strategies but also may provide significant insight into the underlying mechanisms of disease pathogenesis.
    Keywords:  Rheumatoid Arthritis; glycolysis; metabolites; oxidative phosphorylation; synovial tissue
  4. Cancers (Basel). 2022 Jan 04. pii: 250. [Epub ahead of print]14(1):
      The tumor microenvironment (TME) comprises various cell types, soluble factors, viz, metabolites or cytokines, which together play in promoting tumor metastasis. Tumor infiltrating immune cells play an important role against cancer, and metabolic switching in immune cells has been shown to affect activation, differentiation, and polarization from tumor suppressive into immune suppressive phenotypes. Macrophages represent one of the major immune infiltrates into TME. Blood monocyte-derived macrophages and myeloid derived suppressor cells (MDSCs) infiltrating into the TME potentiate hostile tumor progression by polarizing into immunosuppressive tumor-associated macrophages (TAMs). Recent studies in the field of immunometabolism focus on metabolic reprogramming at the TME in polarizing tumor-associated macrophages (TAMs). Lipid droplets (LD), detected in almost every eukaryotic cell type, represent the major source for intra-cellular fatty acids. Previously, LDs were mainly described as storage sites for fatty acids. However, LDs are now recognized to play an integral role in cellular signaling and consequently in inflammation and metabolism-mediated phenotypical changes in immune cells. In recent years, the role of LD dependent metabolism in macrophage functionality and phenotype has been being investigated. In this review article, we discuss fatty acids stored in LDs, their role in modulating metabolism of tumor-infiltrating immune cells and, therefore, in shaping the cancer progression.
    Keywords:  immunosuppression; lipid droplet (LD); metabolic reprogramming; myeloid derived suppressor cells (MDSCs); tumor microenvironment (TME); tumor-associated macrophages (TAMs)
  5. Clin Exp Immunol. 2021 Dec 15. pii: uxab033. [Epub ahead of print]
      Metabolic inflammation, defined as a chronic low-grade inflammation, is implicated in numerous metabolic diseases. In recent years, the role of regulatory T cells (Tregs) as key controllers of metabolic inflammation has emerged, but our comprehension on how different metabolic pathways influence Treg functions needs a deeper understanding. Here we focus on how circulating and intracellular lipid metabolism, in particular cholesterol metabolism, regulates Treg homeostasis, expansion, and functions. Cholesterol is carried through the bloodstream by circulating lipoproteins (chylomicrons, very low-density lipoproteins, low-density lipoproteins). Tregs are equipped with a wide array of metabolic sensors able to perceive and respond to changes in the lipid environment through the activation of different intracellular pathways thus conferring to these cells a crucial metabolic and functional plasticity. Nevertheless, altered cholesterol transport, as observed in genetic dyslipidemias and atherosclerosis, impairs Treg proliferation and function through defective cellular metabolism. The intracellular pathway devoted to the cholesterol synthesis is the mevalonate pathway and several studies have shown that this pathway is essential for Treg stability and suppressive activity. High cholesterol concentrations in the extracellular environment may induce massive accumulation of cholesterol inside the cell thus impairing nutrients sensors and inhibiting the mevalonate pathway. This review summarizes the current knowledge regarding the role of circulating and cellular cholesterol metabolism in the regulation of Treg metabolism and functions. In particular, we will discuss how different pathological conditions affecting cholesterol transport may affect cellular metabolism in Tregs.
    Keywords:  Treg; atherosclerosis; cholesterol; dyslipidemia; lipoproteins
  6. Cell Mol Immunol. 2022 Jan 11.
      Cholesterol is a critical lipid for all mammalian cells, ensuring proper membrane integrity, fluidity, and biochemical function. Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes. However, our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood. This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools. We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages, with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway. We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis. We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions. We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections. We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.
    Keywords:  Cholesterol; Innate Immunity; Macrophages; Metabolism
  7. Int J Mol Sci. 2021 Dec 23. pii: 135. [Epub ahead of print]23(1):
      Cerebral ischemia-reperfusion injury is related to inflammation driven by free mitochondrial DNA. At the same time, the pro-inflammatory activation of macrophages, that is, polarization in the M1 direction, aggravates the cycle of inflammatory damage. They promote each other and eventually transform macrophages/microglia into neurotoxic macrophages by improving macrophage glycolysis, transforming arginine metabolism, and controlling fatty acid synthesis. Therefore, we propose targeting the mtDNA-driven inflammatory response while controlling the metabolic state of macrophages in brain tissue to reduce the possibility of cerebral ischemia-reperfusion injury.
    Keywords:  STING; cerebral ischemia-reperfusion; immune metabolism; inflammation; macrophages; mtDNA
  8. Cells. 2022 Jan 05. pii: 179. [Epub ahead of print]11(1):
      Expression of immune checkpoint proteins restrict immunosurveillance in the tumor microenvironment; thus, FDA-approved checkpoint inhibitor drugs, specifically PD-1/PD-L1 and CTLA-4 inhibitors, promote a cytotoxic antitumor immune response. Aside from inflammatory signaling, immune checkpoint proteins invoke metabolic reprogramming that affects immune cell function, autonomous cancer cell bioenergetics, and patient response. Therefore, this review will focus on the metabolic alterations in immune and cancer cells regulated by currently approved immune checkpoint target proteins and the effect of costimulatory receptor signaling on immunometabolism. Additionally, we explore how diet and the microbiome impact immune checkpoint blockade therapy response. The metabolic reprogramming caused by targeting these proteins is essential in understanding immune-related adverse events and therapeutic resistance. This can provide valuable information for potential biomarkers or combination therapy strategies targeting metabolic pathways with immune checkpoint blockade to enhance patient response.
    Keywords:  bioenergetics; diet; immune checkpoint blockade; immune-related adverse events; immunometabolism; metabolism
  9. Med Microbiol Immunol. 2022 Jan 13.
      Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown. Here, we analyzed the lung single-nucleus RNA-sequencing (snRNA-seq) data of several deceased COVID-19 patients and focused on changes in transcripts associated with cellular metabolism. We observed upregulated glycolysis and oxidative phosphorylation in alveolar type 2 progenitor cells, which may block alveolar epithelial differentiation and surfactant secretion. Elevated inositol phosphate metabolism in airway progenitor cells may promote neutrophil infiltration and damage the lung barrier. Further, multiple metabolic alterations in the airway goblet cells are associated with impaired muco-ciliary clearance. Increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism not only enhance macrophage activation but also contribute to SARS-CoV-2 induced lung injury. The cytotoxicity of natural killer cells and CD8+ T cells may be enhanced by glycerolipid and inositol phosphate metabolism. Glycolytic activation in fibroblasts is related to myofibroblast differentiation and fibrogenesis. Glycolysis, oxidative phosphorylation, and glutathione metabolism may also boost the aging, apoptosis and proliferation of vascular smooth muscle cells, resulting in pulmonary arterial hypertension. In conclusion, this preliminary study revealed a possible cellular metabolic basis for the altered innate immunity, adaptive immunity, and niche cell function in the lung after SARS-CoV-2 infection. Therefore, patients with COVID-19 may benefit from therapeutic strategies targeting cellular metabolism in future.
    Keywords:  COVID-19; Cellular metabolism; Glycolysis; Host immunity; RNA sequencing
  10. Immunity. 2022 Jan 11. pii: S1074-7613(21)00545-8. [Epub ahead of print]55(1): 1-3
      The role of folate-dependent one carbon (1C) metabolism in CD4+ T cell polarization is incompletely understood. In this issue of Immunity, Sugiura et al. (2021) provide evidence that blocking the 1C metabolic enzyme MTHFD2 may curb pro-inflammatory CD4+ T cells, while redirecting them toward a regulatory T cell phenotype.
  11. Cell Rep. 2022 Jan 11. pii: S2211-1247(21)01726-5. [Epub ahead of print]38(2): 110222
      Phagocytosis of apoptotic cells, termed efferocytosis, is critical for tissue homeostasis and drives anti-inflammatory programming in engulfing macrophages. Here, we assess metabolites in naive and inflammatory macrophages following engulfment of multiple cellular and non-cellular targets. Efferocytosis leads to increases in the arginine-derived polyamines, spermidine and spermine, in vitro and in vivo. Surprisingly, polyamine accumulation after efferocytosis does not arise from retention of apoptotic cell metabolites or de novo synthesis but from enhanced polyamine import that is dependent on Rac1, actin, and PI3 kinase. Blocking polyamine import prevents efferocytosis from suppressing macrophage interleukin (IL)-1β or IL-6. This identifies efferocytosis as a trigger for polyamine import and accumulation, and imported polyamines as mediators of efferocytosis-induced immune reprogramming.
    Keywords:  apoptosis; arginine; efferocytosis; macrophage; metabolites; phagocytosis; polyamines
  12. Mol Biol Rep. 2022 Jan 14.
      The amino acid tryptophan (TRP) is critical for the expansion and survival of cells. During the past few years, the manipulation of tryptophan metabolism via indoleamine 2,3 dioxygenase (IDO) has been presented as a significant regulatory mechanism for tolerance stimulation and the regulation of immune responses. Currently, a considerable number of studies suggest that the role of IDO in T helper 2 (Th2) cell regulation may be different from that of T helper 1 (Th1) immune responses. IDO acts as an immunosuppressive tolerogenic enzyme to decrease allergic responses through the stimulation of the Kynurenine-IDO pathway, the subsequent reduction of TRP, and the promotion of Kynurenine products. Kynurenine products motivate T-cell apoptosis and anergy, the propagation of Treg and Th17 cells, and the aberration of the Th1/Th2 response. We suggest that the IDO-kynurenine pathway can function as a negative reaction round for Th1 cells; however, it may play a different role in upregulating principal Th2 immune responses. In this review, we intend to integrate novel results on this pathway in correlation with allergic diseases.
    Keywords:  3-Dioxygenase; Allergic diseases; Indoleamine 2; Kynurenine; Th2-type immunity; Tryptophan
  13. Mol Cell. 2021 Dec 31. pii: S1097-2765(21)01068-6. [Epub ahead of print]
      Citrulline can be converted into argininosuccinate by argininosuccinate synthetase (ASS1) in the urea cycle and the citrulline-nitric oxide cycle. However, the regulation and biological function of citrulline metabolism remain obscure in the immune system. Unexpectedly, we found that macrophage citrulline declines rapidly after interferon gamma (IFN-γ) and/or lipopolysaccharide (LPS) stimulation, which is required for efficient proinflammatory signaling activation. Mechanistically, IFN-γ and/or LPS stimulation promotes signal transducers and activators of transcription 1 (STAT1)-mediated ASS1 transcription and Janus kinase2 (JAK2)-mediated phosphorylation of ASS1 at tyrosine 87, thereby leading to citrulline depletion. Reciprocally, increased citrulline directly binds to JAK2 and inhibits JAK2-STAT1 signaling. Blockage of ASS1-mediated citrulline depletion suppresses the host defense against bacterial infection in vivo. We therefore define a central role for ASS1 in controlling inflammatory macrophage activation and antibacterial defense through depletion of cellular citrulline and, further, identify citrulline as an innate immune-signaling metabolite that engages a metabolic checkpoint for proinflammatory responses.
    Keywords:  ASS1; JAK2-STAT1 signaling; citrulline; metabolite sensing; phosphorylation; proinflammatory macrophage activation; transcriptional regulation
  14. Semin Immunopathol. 2022 Jan 12.
      It has emerged that an interconnected relationship exists between metabolism, circadian rhythms, and the immune system. The relationship between metabolism and circadian rhythms is not that surprising given the necessity to align rhythms of feeding/fasting with activity/rest. Recently, our understanding of the importance of metabolic pathways in terms of immune function, termed immunometabolism, has grown exponentially. It is now appreciated that the time of day during which the innate immune system is challenged strongly conditions the subsequent response. Recent observations have found that many individual components that make up the circadian clock also control aspects of metabolism in innate immune cells to modulate inflammation. This circadian/metabolic axis may be a key factor driving rhythmicity of immune function and circadian disruption is associated with a range of chronic inflammatory diseases such as atherosclerosis, obesity, and diabetes. The field of "circadian immunometabolism" seeks to reveal undiscovered circadian controlled metabolic pathways that in turn regulate immune responses. The innate immune system has been intricately linked to chronic inflammatory diseases, and within the immune system, individual cell types carry out unique roles in inflammation. Therefore, circadian immunometabolism effects are unique to each innate immune cell.
    Keywords:  Circadian immunometabolism; Circadian rhythms; Inflammation; Innate immunity; Metabolism
  15. Molecules. 2021 Dec 28. pii: 152. [Epub ahead of print]27(1):
      Macrophages have diverse functions in the pathogenesis, resolution, and repair of inflammatory processes. Elegant studies have elucidated the metabolomic and transcriptomic profiles of activated macrophages. However, the versatility of macrophage responses in inflammation is likely due, at least in part, to their ability to rearrange their repertoire of bioactive lipids, including fatty acids and oxylipins. This review will describe the fatty acids and oxylipins generated by macrophages and their role in type 1 and type 2 immune responses. We will highlight lipidomic studies that have shaped the current understanding of the role of lipids in macrophage polarization.
    Keywords:  fatty acids; macrophages; oxylipins
  16. Microbiol Spectr. 2022 Jan 12. e0231021
      Under oxidative stress, viruses prefer glycolysis as an ATP source, and glutamine is required as an anaplerotic substrate to replenish the TCA cycle. Infectious spleen and kidney necrosis virus (ISKNV) induces reductive glutamine metabolism in the host cells. Here we report that ISKNV infection the increased NAD+/NADH ratio and the gene expression of glutaminase 1 (GLS1), glutamate dehydrogenase (GDH), and isocitrate dehydrogenase (IDH2) resulted in the phosphorylation and activation of mammalian target of rapamycin (mTOR) in CPB cells. Inhibition of mTOR signaling attenuates ISKNV-induced the upregulation of GLS1, GDH, and IDH2 genes expression, and exhibits significant antiviral activity. Moreover, the expression of silent information regulation 2 homolog 3 (SIRT3) in mRNA level is increased to enhance the reductive glutamine metabolism in ISKNV-infected cells. And those were verified by the expression levels of metabolic genes and the activities of metabolic enzymes in SIRT3-overexpressed or SIRT3-knocked down cells. Remarkably, activation of mTOR signaling upregulates the expression of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene, leading to increased expression of SIRT3 and metabolic genes. These results indicate that mTOR signaling manipulates reductive glutamine metabolism in ISKNV-infected cells through PGC-1α-dependent regulation of SIRT3. Our findings reveal new insights on ISKNV-host interactions and will contribute new cellular targets to antiviral therapy. IMPORTANCE Infectious spleen and kidney necrosis virus (ISKNV) is the causative agent of farmed fish disease that has caused huge economic losses in fresh and marine fish aquaculture. The redox state of cells is shaped by virus into a favorable microenvironment for virus replication and proliferation. Our previous study demonstrated that ISKNV replication induced glutamine metabolism reprogramming, and it is necessary for the ISKNV multiplication. In this study, the mechanistic link between the mTOR/PGC-1α/SIRT3 pathway and reductive glutamine metabolism in the ISKNV-infected cells was provided, which will contribute new insights into the pathogenesis of ISKNV and antiviral treatment strategies.
    Keywords:  ISKNV; PGC-1α; SIRT3; mTOR; reductive glutamine metabolism
  17. Int J Obes (Lond). 2022 Jan 14.
      OBJECTIVES: Metabolic inflammation is a hallmark of obesity and related disorders, afflicting substantial morbidity and mortality to individuals worldwide. White visceral and subcutaneous adipose tissue not only serves as energy storage but also controls metabolism. Adipose tissue inflammation, commonly observed in human obesity, is considered a critical driver of metabolic perturbation while molecular hubs are poorly explored. Metabolic stress evoked by e.g. long-chain fatty acids leads to oxidative perturbation of adipocytes and production of inflammatory cytokines, fuelling macrophage infiltration and systemic low-grade inflammation. Glutathione peroxidase 4 (GPX4) protects against lipid peroxidation, accumulation of oxygen-specific epitopes and cell death, collectively referred to as ferroptosis. Here, we explore the function of adipocyte GPX4 in mammalian metabolism.METHODS: We studied the regulation and function of GPX4 in differentiated mouse adipocytes derived from 3T3-L1 fibroblasts. We generated two conditional adipocyte-specific Gpx4 knockout mice by crossing Gpx4fl/fl mice with Adipoq-Cre+ (Gpx4-/-AT) or Fabp4-Cre+ (Gpx4+/-Fabp4) mice. Both models were metabolically characterized by a glucose tolerance test and insulin resistance test, and adipose tissue lipid peroxidation, inflammation and cell death were assessed by quantifying oxygen-specific epitopes, transcriptional analysis of chemokines, quantification of F4/80+ macrophages and TUNEL labelling.
    RESULTS: GPX4 expression was induced during and required for adipocyte differentiation. In mature adipocytes, impaired GPX4 activity spontaneously evoked lipid peroxidation and expression of inflammatory cytokines such as TNF-α, interleukin 1β (IL-1β), IL-6 and the IL-8 homologue CXCL1. Gpx4-/-AT mice spontaneously displayed adipocyte hypertrophy on a chow diet, which was paralleled by the accumulation of oxygen-specific epitopes and macrophage infiltration in adipose tissue. Furthermore, Gpx4-/-AT mice spontaneously developed glucose intolerance, hepatic insulin resistance and systemic low-grade inflammation, when compared to wildtype littermates, which was similarly recapitulated in Gpx4+/-Fabp4 mice. Gpx4-/-AT mice exhibited no signs of adipocyte death.
    CONCLUSION: Adipocyte GPX4 protects against spontaneous metabolic dysregulation and systemic low-grade inflammation independent from ferroptosis, which could be therapeutically exploited in the future.
  18. JCI Insight. 2022 Jan 11. pii: e151892. [Epub ahead of print]
      Monocyte-derived macrophages are key players in tissue homeostasis and diseases regulated by a variety of signaling molecules. Recent literature has highlighted the ability for biogenic amines to regulate macrophage functions, but the mechanisms governing biogenic amine signaling in and around immune cells remains nebulous. In the central nervous system (CNS), biogenic amine transporters are regarded as the master regulators of neurotransmitter signaling. While we and others have shown that macrophages express these transporters, relatively little is known of their function in these cells. To address these knowledge gaps, we investigated the function of norepinephrine (NET) and dopamine (DAT) transporters on human monocyte-derived macrophages. We found that both NET and DAT are present and can uptake substrate from the extracellular space at baseline. Not only was DAT expressed in cultured monocyte-derived macrophages (MDMs), but it was also detected in a subset of intestinal macrophages in situ. Surprisingly, we discovered a NET-independent, DAT-mediated immuno-modulatory mechanism in response to lipopolysaccharide (LPS). LPS induced reverse transport of dopamine through DAT, engaging an autocrine/paracrine signaling loop that regulated the macrophage response. Removing this signaling loop enhanced the pro-inflammatory response to LPS. Collectively, our data introduce a potential role for DAT in the regulation of innate immunity.
    Keywords:  Inflammation; Innate immunity; Macrophages; Neuroscience; Transport
  19. Cancer Immunol Immunother. 2022 Jan 09.
      Natural killer (NK) cells are cytotoxic innate lymphocytes that are specialized to kill tumor cells. NK cells are responsive to the primary cytokine IL-2 in the tumor microenvironment (TME), to activate its effector functions against tumors. Despite their inherent ability to kill tumor cells, dysfunctional NK cells observed within advanced solid tumors are associated with poor patient survival. Hypoxia in the TME is a major contributor to immune evasion in solid tumors that could contribute to impaired NK cell function. HIF-1α is a nodal regulator of hypoxia in driving the adaptive cellular responses to changes in oxygen concentrations. Whether HIF-1α is expressed in hypoxic NK cells in the context of IL-2 and whether its expression regulates NK cell effector function are unclear. Here, we report that freshly isolated NK cells from human peripheral blood in hypoxia could not stabilize HIF-1α protein coincident with impaired anti-tumor cytotoxicity. However, ex vivo expansion of these cells restored HIF-1α levels in hypoxia to promote antitumor cytotoxic functions. Similarly, the human NK cell line NKL expressed HIF-1α upon IL-2 stimulation in hypoxia and exhibited improved anti-tumor cytotoxicity and IFN-γ secretion. We found that ex vivo expanded human NK cells and NKL cells required the concerted activation of PI3K/mTOR pathway initiated by IL-2 signaling in combination with hypoxia for HIF-1α stabilization. These findings highlight that HIF-1α stabilization in hypoxia maximizes NK cell effector function and raises the prospect of NK cells as ideal therapeutic candidates for solid tumors.
    Keywords:  HIF-1α; Hypoxia; IL-2; Natural killer cells
  20. Int J Biol Sci. 2022 ;18(2): 599-616
      Lactic acid (LA) metabolism in the tumor microenvironment contributes to the establishment and maintenance of immune tolerance. This pathway is characterized in tumor associated macrophages. However, the role and pathway of LA metabolism at maternal-fetal interface during early pregnancy, especially in decidual macrophage differentiation, are still unclear. Herein, for the first time, we discovered that LA can trigger either M2 or M1 macrophage polarization via oxidative phosphorylation and glycolysis regulation under normoxia or hypoxia, respectively. Also, LA metabolism played a vital role in decidual macrophages-mediated recurrent pregnancy loss (RPL), through HIF-1α/SRC/LDHA pathway. Moreover, blockade of LA intake with AZD3965 (MCT-1 inhibitor) could rescue pregnancy in an abortion-prone mouse model, suggesting a potential therapeutic target in RPL. Collectively, the present study identifies the previously unknown functions of LA metabolism in the differentiation of decidual macrophages in early normal pregnancy and RPL, and provides a potential therapeutic strategy in RPL by manipulating decidual macrophages' functions through LA metabolic pathway.
    Keywords:  decidual macrophage; early pregnancy; lactic acid; recurrent pregnancy loss; trophoblast
  21. Nat Commun. 2022 Jan 10. 13(1): 139
      Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation.
  22. RSC Med Chem. 2021 Dec 15. 12(12): 2053-2059
      Endogenous itaconate as well as the gasotransmitter CO have recently been described as powerful anti-inflammatory and immunomodulating agents. However, each of the two agents comes along with a major drawback: Whereas itaconates only exert beneficial effects at high concentrations above 100 μM, the uncontrolled application of CO has strong toxic effects. To solve these problems, we designed hybrid prodrugs, i.e. itaconates that are conjugated with an esterase-triggered CO-releasing acyloxycyclohexadiene-Fe(CO)3 unit (ItaCORMs). Here, we describe the synthesis of different ItaCORMs and demonstrate their anti-inflammatory potency in cellular assays of primary murine immune cells in the low μmolar range (<10 μM). Thus, ItaCORMs represent a promising new class of hybrid compounds with high clinical potential as anti-inflammatory agents.
  23. ACS Appl Bio Mater. 2020 Nov 16. 3(11): 7562-7574
      The field of bone tissue engineering has seen the advancement of a variety of biomaterials with a diverse range of material properties. Biomaterial properties such as particle shape and size, stiffness, and pore size all influence the osteogenic capacity of biomaterials, typically evaluated in vitro by analyzing their potential to promote osteogenesis in mesenchymal stem cells (MSCs). There is now accumulating evidence highlighting the role of macrophages in driving bone regeneration responses. In this study, we evaluated the osteogenic capacity of collagen scaffolds functionalized with hydroxyapatite particles of varying shapes (needle vs spherical) and sizes (5 μm vs 100 μm) using an in vitro culture system of MSCs alone and in coculture with macrophages. We show that macrophage response to HA particles was elevated in the presence of a scaffold with 5 μm needle-shaped particles (Coll N5), with an increase in the expression and secretion of both pro-inflammatory (TNFα, IL6, and MIP1α) and anti-inflammatory (IL10 and IL1Ra) factors. When MSCs alone were cultured on the scaffolds, we show that scaffolds with HA particles were highly osteogenic, with superior osteogenesis observed in scaffolds with large 30 μm spherical particles (Coll S30) compared to small 5 μm needle-shaped particles (Coll N5). A coculture of MSCs with macrophages increased osteogenesis in all groups, with the most dramatic increase on Coll N5 scaffolds, leading to an elimination of the differences observed during monoculture. Through gene expression analysis, we showed that this correlated with an enhanced pro-osteogenic macrophage phenotype on Coll N5 scaffolds. These results highlight the potential of modulating material properties such as particle shape and size to develop osteoimmunomodulatory materials that direct osteogenic responses by influencing macrophage response.
    Keywords:  bone biomaterials; collagen-hydroxyapatite; hydroxyapatite; immune response; in vitro osteogenesis; macrophage polarization; osteoimmunomodulation
  24. PLoS Pathog. 2022 Jan 13. 18(1): e1010219
      Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. Itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.
  25. iScience. 2022 Jan 21. 25(1): 103607
      Natural control of HIV-1 is a characteristic of <1% of HIV-1-infected individuals, so called elite controllers (EC). In this study, we sought to identify signaling pathways associated with the EC phenotype using integrative proteo-transcriptomic analysis and immunophenotyping. We found HIF signaling and glycolysis as specific traits of the EC phenotype together with dysregulation of HIF target gene transcription. A higher proportion of HIF-1α and HIF-1β in the nuclei of CD4+ and CD8+ T cells in the male EC were observed, indicating a potential increased activation of the HIF signaling pathway. Furthermore, intracellular glucose levels were elevated in EC even as the surface expression of the metabolite transporters Glut1 and MCT-1 were decreased on lymphocytes indicative of unique metabolic uptake and flux profile. Combined, our data show that glycolytic modulation and altered HIF signaling is a unique feature of the male EC phenotype that may contribute to natural control of HIV-1.
    Keywords:  Glycobiology; Immunology; Molecular biology; Omics; Virology
  26. Nat Commun. 2022 Jan 11. 13(1): 215
      Macrophages are integral to the pathogenesis of atherosclerosis, but the contribution of distinct macrophage subsets to disease remains poorly defined. Using single cell technologies and conditional ablation via a LysMCre+ Clec4a2flox/DTR mouse strain, we demonstrate that the expression of the C-type lectin receptor CLEC4A2 is a distinguishing feature of vascular resident macrophages endowed with athero-protective properties. Through genetic deletion and competitive bone marrow chimera experiments, we identify CLEC4A2 as an intrinsic regulator of macrophage tissue adaptation by promoting a bias in monocyte-to-macrophage in situ differentiation towards colony stimulating factor 1 (CSF1) in vascular health and disease. During atherogenesis, CLEC4A2 deficiency results in loss of resident vascular macrophages and their homeostatic properties causing dysfunctional cholesterol metabolism and enhanced toll-like receptor triggering, exacerbating disease. Our study demonstrates that CLEC4A2 licenses monocytes to join the vascular resident macrophage pool, and that CLEC4A2-mediated macrophage homeostasis is critical to combat cardiovascular disease.
  27. Commun Biol. 2022 Jan 11. 5(1): 27
      Despite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic flexibility and adaptation in people living with HIV (PLWH). Our study investigated alterations in the plasma metabolic profiles by comparing PLWH on long-term cART(>5 years) and matched HIV-negative controls (HC) in two cohorts from low- and middle-income countries (LMIC), Cameroon, and India, respectively, to understand the system-level dysregulation in HIV-infection. Using untargeted and targeted LC-MS/MS-based metabolic profiling and applying advanced system biology methods, an altered amino acid metabolism, more specifically to glutaminolysis in PLWH than HC were reported. A significantly lower level of neurosteroids was observed in both cohorts and could potentiate neurological impairments in PLWH. Further, modulation of cellular glutaminolysis promoted increased cell death and latency reversal in pre-monocytic HIV-1 latent cell model U1, which may be essential for the clearance of the inducible reservoir in HIV-integrated cells.
  28. Gastroenterology. 2022 Jan 11. pii: S0016-5085(22)00012-9. [Epub ahead of print]
      BACKGROUND & AIMS: Crohn's disease (CD) globally emerges with Westernization of lifestyle and nutritional habits. However, a specific dietary constituent that comprehensively evokes gut inflammation in human IBD remains elusive. Here, we aimed at delineating how increased intake of polyunsaturated fatty acids (PUFAs) in a Western diet, known to impart risk for developing CD, impacts gut inflammation and disease course. We hypothesized that the unfolded protein response and anti-oxidative activity of Glutathione peroxidase 4 (GPX4), which are compromised in human CD epithelium, compensates for metabolic perturbation evoked by dietary PUFAs.METHODS: We phenotyped and mechanistically dissected enteritis evoked by a PUFA-enriched Western diet in two mouse models exhibiting endoplasmic reticulum (ER) stress consequent to intestinal epithelial cell (IEC)-specific deletion of X-box-binding protein 1 (Xbp1) or Gpx4. We translated findings to human CD epithelial organoids and correlated PUFA intake, estimated by a dietary questionnaire or stool metabolomics, with clinical disease course in two independent CD cohorts.
    RESULTS: PUFA excess in a Western diet potently induced ER stress, driving enteritis in Xbp1-/-IEC and in Gpx4+/-IEC mice. ω-3 and ω-6 PUFAs activated the epithelial endoplasmic reticulum sensor IRE1α by toll-like receptor 2 (TLR2) sensing of oxygen specific epitopes. TLR2-controlled IRE1α activity governed PUFA-induced chemokine production and enteritis. In active human CD, ω-3 and ω-6 PUFAs instigated epithelial chemokine expression and patients displayed a compatible inflammatory stress signature in the serum. Estimated PUFA intake correlated with clinical and biochemical disease activity in a cohort of 160 CD patients, which was similarly demonstrable in an independent metabolomic stool analysis from 199 CD patients.
    CONCLUSION: We provide evidence for the concept of PUFA-induced metabolic gut inflammation which may worsen the course of human CD. Our findings provide a basis for targeted nutritional therapy.
    Keywords:  X-box binding protein 1; endoplasmic reticulum stress; glutathione peroxidase 4; ω-3 polyunsaturated fatty acids; ω-6 polyunsaturated fatty acids
  29. Cell Death Differ. 2022 Jan 14.
      Heme is an erythrocyte-derived toxin that drives disease progression in hemolytic anemias, such as sickle cell disease. During hemolysis, specialized bone marrow-derived macrophages with a high heme-metabolism capacity orchestrate disease adaptation by removing damaged erythrocytes and heme-protein complexes from the blood and supporting iron recycling for erythropoiesis. Since chronic heme-stress is noxious for macrophages, erythrophagocytes in the spleen are continuously replenished from bone marrow-derived progenitors. Here, we hypothesized that adaptation to heme stress progressively shifts differentiation trajectories of bone marrow progenitors to expand the capacity of heme-handling monocyte-derived macrophages at the expense of the homeostatic generation of dendritic cells, which emerge from shared myeloid precursors. This heme-induced redirection of differentiation trajectories may contribute to hemolysis-induced secondary immunodeficiency. We performed single-cell RNA-sequencing with directional RNA velocity analysis of GM-CSF-supplemented mouse bone marrow cultures to assess myeloid differentiation under heme stress. We found that heme-activated NRF2 signaling shifted the differentiation of bone marrow cells towards antioxidant, iron-recycling macrophages, suppressing the generation of dendritic cells in heme-exposed bone marrow cultures. Heme eliminated the capacity of GM-CSF-supplemented bone marrow cultures to activate antigen-specific CD4 T cells. The generation of functionally competent dendritic cells was restored by NRF2 loss. The heme-induced phenotype of macrophage expansion with concurrent dendritic cell depletion was reproduced in hemolytic mice with sickle cell disease and spherocytosis and associated with reduced dendritic cell functions in the spleen. Our data provide a novel mechanistic underpinning of hemolytic stress as a driver of hyposplenism-related secondary immunodeficiency.
  30. Mol Ther. 2022 Jan 07. pii: S1525-0016(22)00007-7. [Epub ahead of print]
      The effect of immunotherapy is limited by oncometabolite D-2-hydroxyglutarate (D2HG). D2HGDH is an inducible enzyme that converts D2HG into the endogenous metabolite 2-oxoglutarate. We aimed to evaluate the impairment of CD8 T lymphocyte function in the high-D2HG environment and to explore the phenotypic features and anti-tumor effect of D2HGDH-modified CAR-T cells. D2HG treatment inhibited the expansion of human CD8 T lymphocytes and CAR-T cells , increased their glucose uptake, suppressed effector cytokine production, and decreased the central memory cell proportion. D2HGDH-modified CAR-T cells displayed distinct phenotypes since D2HGDH knock-out (KO) CAR-T cells exhibited significant decrease in central memory cell differentiation and intracellular cytokine production, while D2HGDH over-expression (OE) CAR-T cells showed predominant killing efficacy against NALM6 cancer cells in high-D2HG medium. In vivo xenograft experiments confirmed D2HGDH-OE CAR-T cell decreased serum D2HG and improved the overall survival of mice bearing NALM6 cancer cells with mutation IDH1. Our findings demonstrated immunosuppressive effect of D2HG and distinct phenotype of D2HGDH modified CAR-T cells. D2HGDH-OE CAR-T cells can take advantage of the catabolism of D2HG to foster T cell expansion, function, and anti-tumor effectiveness.
    Keywords:  Chimeric antigen receptor; D-2-hydroxyglutarate; D2HGDH; Immunotherapy; Oncometabolites
  31. iScience. 2022 Jan 21. 25(1): 103722
      SARS-CoV-2 is a newly identified coronavirus that causes the respiratory disease called coronavirus disease 2019 (COVID-19). With an urgent need for therapeutics, we lack a full understanding of the molecular basis of SARS-CoV-2-induced cellular damage and disease progression. Here, we conducted transcriptomic analysis of human PBMCs, identified significant changes in mitochondrial, ion channel, and protein quality-control gene products. SARS-CoV-2 proteins selectively target cellular organelle compartments, including the endoplasmic reticulum and mitochondria. M-protein, NSP6, ORF3A, ORF9C, and ORF10 bind to mitochondrial PTP complex components cyclophilin D, SPG-7, ANT, ATP synthase, and a previously undescribed CCDC58 (coiled-coil domain containing protein 58). Knockdown of CCDC58 or mPTP blocker cyclosporin A pretreatment enhances mitochondrial Ca2+ retention capacity and bioenergetics. SARS-CoV-2 infection exacerbates cardiomyocyte autophagy and promotes cell death that was suppressed by cyclosporin A treatment. Our findings reveal that SARS-CoV-2 viral proteins suppress cardiomyocyte mitochondrial function that disrupts cardiomyocyte Ca2+ cycling and cell viability.
    Keywords:  Cardiovascular medicine; Transcriptomics; Virology
  32. Inflamm Res. 2022 Jan 09.
      Ethyl pyruvate (EP) has potent influence on redox processes, cellular metabolism, and inflammation. It has been intensively studied in numerous animal models of systemic and organ-specific disorders whose pathogenesis involves a strong immune component. Here, basic chemical and biological properties of EP are discussed, with an emphasis on its redox and metabolic activity. Further, its influence on myeloid and T cells is considered, as well as on intracellular signaling beyond its effect on immune cells. Also, the effects of EP on animal models of chronic inflammatory and autoimmune disorders are presented. Finally, a possibility to apply EP as a treatment for such diseases in humans is discussed. Scientific papers cited in this review were identified using the PubMed search engine that relies on the MEDLINE database. The reference list covers the most important findings in the field in the past twenty years.
    Keywords:  Autoimmunity; Ethyl pyruvate; Inflammation; Metabolism; Redox
  33. JCI Insight. 2022 Jan 11. pii: e152800. [Epub ahead of print]
      Type 1 diabetes is an autoimmune disease characterized by insulin-producing beta-cell destruction. While islet transplantation restores euglycemia and improves patient outcomes, an ideal transplant site remains elusive. Brown adipose tissue (BAT) is a highly vascularized and anti-inflammatory microenvironment. As these tissue features can promote islet graft survival, we hypothesize that islets transplanted into BAT will maintain islet graft and BAT function, while delaying immune-mediated rejection. We performed syngeneic and allogeneic islet transplants into BAT or under the kidney capsule of streptozotocin (STZ)-induced diabetic NOD.Rag and NOD mice to investigate islet graft function, BAT function, metabolism, and immune-mediated rejection. Islet grafts within BAT restored euglycemia similarly to kidney capsule controls. Islets transplanted in BAT maintained expression of islet hormones, transcription factors, and were vascularized. Compared to kidney capsule and euglycemic mock surgery controls, no differences in glucose or insulin tolerance, thermogenic regulation, or energy expenditure were observed with islet grafts in BAT. Immune profiling of BAT revealed enriched anti-inflammatory macrophages and T cells. Compared to kidney capsule, islets transplanted in BAT demonstrated significant delays in autoimmune and allograft rejection, possibly due to increased anti-inflammatory immune populations. Our data support BAT as an alternative islet transplantation site that may improve graft survival.
    Keywords:  Autoimmune diseases; Endocrinology; Glucose metabolism; Islet cells; Transplantation
  34. J Clin Invest. 2022 Jan 13. pii: e139828. [Epub ahead of print]
      BACKGROUND: Fasting and NAD+-boosting compounds including NAD+ precursor nicotinamide riboside (NR) confer anti-inflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODS: We explored the underlying biology in myeloid cells from healthy volunteers following in-vivo placebo or NR administration and subsequently tested the findings in-vitro in monocytes extracted from subjects with systemic lupus erythematosus (SLE).
    RESULTS: RNA sequencing of unstimulated and lipopolysaccharide (LPS)-activated monocytes implicate NR in the regulation of autophagy and type I interferon signaling. In primary monocytes NR blunts LPS-induced IFNβ production and genetic or pharmacologic disruption of autophagy phenocopies this effect. Given NAD+ is a co-enzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased inosine level. Inosine supplementation similarly blunts autophagy and IFNβrelease. Finally, as SLE exhibits type I interferon dysregulation, we assessed the NR effect on SLE patient monocytes and found that NR reduces autophagy and interferon-β release.
    CONCLUSION: We conclude that NR, in an NAD+-dependent manner and in part via inosine-signaling, mediates suppression of autophagy and attenuates type I interferon in myeloid cells and identifies NR as a potential adjunct for SLE management.
    TRIAL REGISTRATION: registration numbers: NCT02812238, NCT00001846 and NCT00001372.
    FUNDING: This work was supported by the NHLBI and NIAMS Divisions of Intramural Research.
    Keywords:  Autophagy; Cytokines; Inflammation; Innate immunity; Metabolism
  35. Cells. 2021 Dec 21. pii: 4. [Epub ahead of print]11(1):
      The nuclear receptor PPARα is associated with reducing adiposity, especially in the liver, where it transactivates genes for β-oxidation. Contrarily, the function of PPARα in extrahepatic tissues is less known. Therefore, we established the first adipose-specific PPARα knockout (PparaFatKO) mice to determine the signaling position of PPARα in adipose tissue expansion that occurs during the development of obesity. To assess the function of PPARα in adiposity, female and male mice were placed on a high-fat diet (HFD) or normal chow for 30 weeks. Only the male PparaFatKO animals had significantly more adiposity in the inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) with HFD, compared to control littermates. No changes in adiposity were observed in female mice compared to control littermates. In the males, the loss of PPARα signaling in adipocytes caused significantly higher cholesterol esters, activation of the transcription factor sterol regulatory element-binding protein-1 (SREBP-1), and a shift in macrophage polarity from M2 to M1 macrophages. We found that the loss of adipocyte PPARα caused significantly higher expression of the Per-Arnt-Sim kinase (PASK), a kinase that activates SREBP-1. The hyperactivity of the PASK-SREBP-1 axis significantly increased the lipogenesis proteins fatty acid synthase (FAS) and stearoyl-Coenzyme A desaturase 1 (SCD1) and raised the expression of genes for cholesterol metabolism (Scarb1, Abcg1, and Abca1). The loss of adipocyte PPARα increased Nos2 in the males, an M1 macrophage marker indicating that the population of macrophages had changed to proinflammatory. Our results demonstrate the first adipose-specific actions for PPARα in protecting against lipogenesis, inflammation, and cholesterol ester accumulation that leads to adipocyte tissue expansion in obesity.
    Keywords:  FAS; SCD1; adipocyte; adipogenesis; cholesterol esters; fatty acid synthase; inflammation; lipid signaling; obesity; sexual dimorphism
  36. JCI Insight. 2022 Jan 11. pii: e150041. [Epub ahead of print]
      Mitophagy and mitochondrial integrated stress response (ISR) are two primary protective mechanisms to maintain functional mitochondria. Whether these two processes are coordinately regulated remains unclear. Here we show that mitochondrial fission 1 protein (Fis1), which is required for completion of mitophagy, serves as a signaling hub linking mitophagy and ISR. In mouse hepatocytes, high fat diet (HFD) feeding induces unresolved oxidative stress, defective mitophagy and enhanced type I interferon (IFN-I) response implicated in promoting metabolic inflammation. Adenoviral-mediated acute hepatic Fis1 over-expression is sufficient to reduce oxidative damage and improve glucose homeostasis in HFD fed mice. RNA-seq analysis reveals that Fis1 triggers a retrograde mitochondria-to-nucleus communication upregulating ISR genes encoding anti-oxidant defense, redox homeostasis and proteostasis pathways. Fis1-mediated ISR also suppresses expression of IFN-I stimulated genes through Atf5, which inhibits the transactivation activity of Irf3 known to control IFN-I production. Metabolite analysis demonstrates that Fis1 activation leads to accumulation of fumarate, a TCA cycle intermediate capable of increasing Atf5 activity. Consequently, hepatic Atf5 over-expression or monomethyl fumarate (MMF) treatment improves glucose homeostasis in HFD fed mice. Collectively, these results support the potential use of small molecules targeting the Fis1-Atf5 axis, such as MMF, to treat metabolic diseases.
    Keywords:  Glucose metabolism; Metabolism; Mitochondria; Obesity
  37. J Exp Med. 2022 Feb 07. pii: e20210909. [Epub ahead of print]219(2):
      Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22-producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ-producing group 1 ILCs (ILC1s) contributes to gut homeostasis. The gut mucosa is characterized by physiological hypoxia, and adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs). However, the impact of HIFs on ILC phenotype and gut homeostasis is not well understood. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ-expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22-expressing, RORγt+, NKp46+ ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1α in NKp46+ cells prevents ILC3-to-ILC1 conversion, increases the expression of IL-22-inducible genes, and confers protection against intestinal damage. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut.