bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023–01–01
fourteen papers selected by
Dylan Ryan, University of Cambridge
  1. SREBP signaling is essential for effective B cell responses.
  2. Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.
  3. Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells.
  4. Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses.
  5. NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation.
  6. Inflammation driven metabolic regulation and adaptation in macrophages.
  7. Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages.
  8. Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.
  9. Modulating T-bet-promoted energy metabolism in pathogenic age/autoimmune-associated B cells ameliorates lupus autoimmunity.
  10. Fatty acid composition and metabolic partitioning of α-linolenic acid are contingent on life stage in human CD3+ T lymphocytes.
  11. The role of metabolism on regulatory T cell development and its impact in tumor and transplantation immunity.
  12. Short-chain fatty acid-mediated epigenetic modulation of inflammatory T cells in vitro.
  13. Pyruvate kinase M2 mediates IL-17 signaling in keratinocytes driving psoriatic skin inflammation.
  14. Editorial: Lactate metabolism and regulation of the immune response.
  1. Nat Immunol. 2022 Dec 28.
    SREBP signaling is essential for effective B cell responses.
    Wei Luo, Julia Z Adamska, Chunfeng Li, Rohit Verma, Qing Liu, Thomas Hagan, Florian Wimmers, Shakti Gupta, Yupeng Feng, Wenxia Jiang, Jiehao Zhou, Erika Valore, Yanli Wang, Meera Trisal, Shankar Subramaniam, Timothy F Osborne, Bali Pulendran.
      Our previous study using systems vaccinology identified an association between the sterol regulatory binding protein (SREBP) pathway and humoral immune response to vaccination in humans. To investigate the role of SREBP signaling in modulating immune responses, we generated mice with B cell- or CD11c+ antigen-presenting cell (APC)-specific deletion of SCAP, an essential regulator of SREBP signaling. Ablation of SCAP in CD11c+ APCs had no effect on immune responses. In contrast, SREBP signaling in B cells was critical for antibody responses, as well as the generation of germinal centers,memory B cells and bone marrow plasma cells. SREBP signaling was required for metabolic reprogramming in activated B cells. Upon mitogen stimulation, SCAP-deficient B cells could not proliferate and had decreased lipid rafts. Deletion of SCAP in germinal center B cells using AID-Cre decreased lipid raft content and cell cycle progression. These studies provide mechanistic insights coupling sterol metabolism with the quality and longevity of humoral immunity.
    DOI:  https://doi.org/10.1038/s41590-022-01376-y
  2. Cell Metab. 2022 Dec 21. pii: S1550-4131(22)00542-3. [Epub ahead of print]
    Metabolic adaptation supports enhanced macrophage efferocytosis in limited-oxygen environments.
    Ya-Ting Wang, Alissa J Trzeciak, Waleska Saitz Rojas, Pedro Saavedra, Yan-Ting Chen, Rachel Chirayil, Jon Iker Etchegaray, Christopher D Lucas, Daniel J Puleston, Kayvan R Keshari, Justin S A Perry.
      Apoptotic cell (AC) clearance (efferocytosis) is performed by phagocytes, such as macrophages, that inhabit harsh physiological environments. Here, we find that macrophages display enhanced efferocytosis under prolonged (chronic) physiological hypoxia, characterized by increased internalization and accelerated degradation of ACs. Transcriptional and translational analyses revealed that chronic physiological hypoxia induces two distinct but complimentary states. The first, "primed" state, consists of concomitant transcription and translation of metabolic programs in AC-naive macrophages that persist during efferocytosis. The second, "poised" state, consists of transcription, but not translation, of phagocyte function programs in AC-naive macrophages that are translated during efferocytosis. Mechanistically, macrophages efficiently flux glucose into a noncanonical pentose phosphate pathway (PPP) loop to enhance NADPH production. PPP-derived NADPH directly supports enhanced efferocytosis under physiological hypoxia by ensuring phagolysosomal maturation and redox homeostasis. Thus, macrophages residing under physiological hypoxia adopt states that support cell fitness and ensure performance of essential homeostatic functions rapidly and safely.
    Keywords:  apoptotic cell clearance; cellular adaptation; efferocytosis; homeostasis; metabolism; oxygen; pentose phosphate pathway; physiological hypoxia
    DOI:  https://doi.org/10.1016/j.cmet.2022.12.005
  3. Nat Immunol. 2022 Dec 28.
    Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells.
    Myeong Joon Kim, Kyungsoo Kim, Hyo Jin Park, Gil-Ran Kim, Kyeong Hee Hong, Ji Hoon Oh, Jimin Son, Dong Jin Park, Dahae Kim, Je-Min Choi, Insuk Lee, Sang-Jun Ha.
      Regulatory T (Treg) cells have an immunosuppressive function and highly express the immune checkpoint receptor PD-1 in the tumor microenvironment; however, the function of PD-1 in tumor-infiltrating (TI) Treg cells remains controversial. Here, we showed that conditional deletion of PD-1 in Treg cells delayed tumor progression. In Pdcd1fl/flFoxp3eGFP-Cre-ERT2(+/-) mice, in which both PD-1-expressing and PD-1-deficient Treg cells coexisted in the same tissue environment, conditional deletion of PD-1 in Treg cells resulted in impairment of the proliferative and suppressive capacity of TI Treg cells. PD-1 antibody therapy reduced the TI Treg cell numbers, but did not directly restore the cytokine production of TI CD8+ T cells in TC-1 lung cancer. Single-cell analysis indicated that PD-1 signaling promoted lipid metabolism, proliferation and suppressive pathways in TI Treg cells. These results suggest that PD-1 ablation or inhibition can enhance antitumor immunity by weakening Treg cell lineage stability and metabolic fitness in the tumor microenvironment.
    DOI:  https://doi.org/10.1038/s41590-022-01373-1
  4. J Exp Med. 2023 Mar 06. pii: e20221073. [Epub ahead of print]220(3):
    Amino acid availability acts as a metabolic rheostat to determine the magnitude of ILC2 responses.
    Suzanne H Hodge, Maria Z Krauss, Irem Kaymak, James I King, Andrew J M Howden, Gordana Panic, Richard K Grencis, Jonathan R Swann, Linda V Sinclair, Matthew R Hepworth.
      Group 2 innate lymphoid cells (ILC2) are functionally poised, tissue-resident lymphocytes that respond rapidly to damage and infection at mucosal barrier sites. ILC2 reside within complex microenvironments where they are subject to cues from both the diet and invading pathogens-including helminths. Emerging evidence suggests ILC2 are acutely sensitive not only to canonical activating signals but also perturbations in nutrient availability. In the context of helminth infection, we identify amino acid availability as a nutritional cue in regulating ILC2 responses. ILC2 are found to be uniquely preprimed to import amino acids via the large neutral amino acid transporters Slc7a5 and Slc7a8. Cell-intrinsic deletion of these transporters individually impaired ILC2 expansion, while concurrent loss of both transporters markedly impaired the proliferative and cytokine-producing capacity of ILC2. Mechanistically, amino acid uptake determined the magnitude of ILC2 responses in part via tuning of mTOR. These findings implicate essential amino acids as a metabolic requisite for optimal ILC2 responses within mucosal barrier tissues.
    DOI:  https://doi.org/10.1084/jem.20221073
  5. Redox Biol. 2022 Dec 16. pii: S2213-2317(22)00347-0. [Epub ahead of print]59 102575
    NCoR1 controls immune tolerance in conventional dendritic cells by fine-tuning glycolysis and fatty acid oxidation.
    Kaushik Sen, Rashmirekha Pati, Atimukta Jha, Gyan Prakash Mishra, Subhasish Prusty, Shweta Chaudhary, Swati Swetalika, Sreeparna Podder, Aishwarya Sen, Mamuni Swain, Ranjan Kumar Nanda, Sunil K Raghav.
      Dendritic cells (DCs) undergo rapid metabolic reprogramming to generate signal-specific immune responses. The fine control of cellular metabolism underlying DC immune tolerance remains elusive. We have recently reported that NCoR1 ablation generates immune-tolerant DCs through enhanced IL-10, IL-27 and SOCS3 expression. In this study, we did comprehensive metabolic profiling of these tolerogenic DCs and identified that they meet their energy requirements through enhanced glycolysis and oxidative phosphorylation (OXPHOS), supported by fatty acid oxidation-driven oxygen consumption. In addition, the reduced pyruvate and glutamine oxidation with a broken TCA cycle maintains the tolerogenic state of the cells. Mechanistically, the AKT-mTOR-HIF-1α-axis mediated glycolysis and CPT1a-driven β-oxidation were enhanced in these tolerogenic DCs. To confirm these observations, we used synthetic metabolic inhibitors and found that the combined inhibition of HIF-1α and CPT1a using KC7F2 and etomoxir, respectively, compromised the overall transcriptional signature of immunological tolerance including the regulatory cytokines IL-10 and IL-27. Functionally, treatment of tolerogenic DCs with dual KC7F2 and etomoxir treatment perturbed the polarization of co-cultured naïve CD4+ T helper (Th) cells towards Th1 than Tregs, ex vivo and in vivo. Physiologically, the Mycobacterium tuberculosis (Mtb) infection model depicted significantly reduced bacterial burden in BMcDC1 ex vivo and in CD103+ lung DCs in Mtb infected NCoR1DC-/-mice. The spleen of these infected animals also showed increased Th1-mediated responses in the inhibitor-treated group. These findings suggested strong involvement of NCoR1 in immune tolerance. Our validation in primary human monocyte-derived DCs (moDCs) showed diminished NCOR1 expression in dexamethasone-derived tolerogenic moDCs along with suppression of CD4+T cell proliferation and Th1 polarization. Furthermore, the combined KC7F2 and etomoxir treatment rescued the decreased T cell proliferative capacity and the Th1 phenotype. Overall, for the first time, we demonstrated here that NCoR1 mediated control of glycolysis and fatty acid oxidation fine-tunes immune tolerance versus inflammation balance in murine and human DCs.
    Keywords:  FAO; Glycolysis; HIF-1α; NCoR1; OXPHOS; Th1; Tregs
    DOI:  https://doi.org/10.1016/j.redox.2022.102575
  6. Clin Immunol. 2022 Dec 23. pii: S1521-6616(22)00297-2. [Epub ahead of print] 109216
    Inflammation driven metabolic regulation and adaptation in macrophages.
    Saloni Gupta, Pranita P Sarangi.
      Macrophages are a diverse population of phagocytic immune cells involved in the host defense mechanisms and regulation of homeostasis. Usually, macrophages maintain healthy functioning at the cellular level, but external perturbation in their balanced functions can lead to acute and chronic disease conditions. By sensing the cues from the tissue microenvironment, these phagocytes adopt a plethora of phenotypes, such as inflammatory or M1 to anti-inflammatory (immunosuppressive) or M2 subtypes, to fulfill their spectral range of functions. The existing evidence in the literature supports that in macrophages, regulation of metabolic switches and metabolic adaptations are associated with their functional behaviors under various physiological and pathological conditions. Since these macrophages play a crucial role in many disorders, therefore it is necessary to understand their heterogeneity and metabolic reprogramming. Consequently, these macrophages have also emerged as a promising target for diseases in which their role is crucial in driving the disease pathology and outcome (e.g., Cancers). In this review, we discuss the recent findings that link many metabolites with macrophage functions and highlight how this metabolic reprogramming can improve our understanding of cellular malfunction in the macrophages during inflammatory disorders. A systematic analysis of the interconnecting crosstalk between metabolic pathways with macrophages should inform the selection of immunomodulatory therapies for inflammatory diseases.
    Keywords:  Inflammatory diseases; Krebs cycle; Macrophages; Metabolic reprogramming; Therapeutics
    DOI:  https://doi.org/10.1016/j.clim.2022.109216
  7. Redox Biol. 2022 Dec 24. pii: S2213-2317(22)00363-9. [Epub ahead of print]59 102591
    Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages.
    Sjors Maassen, Britt Coenen, Melina Ioannidis, Karl Harber, Pieter Grijpstra, Jan Van den Bossche, Geert van den Bogaart.
      Pathological conditions associated with dysfunctional wound healing are characterized by impaired remodelling of extracellular matrix (ECM), increased macrophage infiltration, and chronic inflammation. Macrophages also play an important role in wound healing as they drive wound closure by secretion of molecules like transforming growth factor beta-1 (TGF-β). As the functions of macrophages are regulated by their metabolism, local administration of small molecules that alter this might be a novel approach for treatment of wound-healing disorders. Itaconate is a tricarboxylic acid (TCA) cycle-derived metabolite that has been associated with resolution of macrophage-mediated inflammation. However, its effects on macrophage wound healing functions are unknown. In this study, we investigated the effects of the membrane-permeable 4-octyl itaconate (4-OI) derivative on ECM scavenging by cultured human blood monocyte-derived macrophages (hMDM). We found that 4-OI reduced signalling of p38 mitogen-activated protein kinase (MAPK) induced by the canonical immune stimulus lipopolysaccharide (LPS). Likely as a consequence of this, the production of the inflammatory mediators like tumor necrosis factor (TNF)-α and cyclooxygenase (COX)-2 were also reduced. On the transcriptional level, 4-OI increased expression of the gene coding for TGF-β (TGFB1), whereas expression of the collagenase matrix metalloprotease-8 (MMP8) was reduced. Furthermore, surface levels of the anti-inflammatory marker CD36, but not CD206 and CD11c, were increased in these cells. To directly investigate the effect of 4-OI on scavenging of ECM by macrophages, we developed an assay to measure uptake of fibrous collagen. We observed that LPS promoted collagen uptake and that this was reversed by 4-OI-induced signaling of nuclear factor erythroid 2-related factor 2 (NRF2), a regulator of cellular resistance to oxidative stress and the reduced glycolytic capacity of the macrophage. These results indicate that 4-OI lowers macrophage inflammation, likely promoting a more wound-resolving phenotype.
    DOI:  https://doi.org/10.1016/j.redox.2022.102591
  8. Front Immunol. 2022 ;13 1046755
    Targeting T-cell metabolism to boost immune checkpoint inhibitor therapy.
    Haohao Li, Alison Zhao, Menghua Li, Lizhi Shi, Qiuju Han, Zhaohua Hou.
      Immune checkpoint inhibitors (ICIs) have shown promising therapeutic effects in the treatment of advanced solid cancers, but their overall response rate is still very low for certain tumor subtypes, limiting their clinical scope. Moreover, the high incidence of drug resistance (including primary and acquired) and adverse effects pose significant challenges to the utilization of these therapies in the clinic. ICIs enhance T cell activation and reverse T cell exhaustion, which is a complex and multifactorial process suggesting that the regulatory mechanisms of ICI therapy are highly heterogeneous. Recently, metabolic reprogramming has emerged as a novel means of reversing T-cell exhaustion in the tumor microenvironment; there is increasing evidence that T cell metabolic disruption limits the therapeutic effect of ICIs. This review focuses on the crosstalk between T-cell metabolic reprogramming and ICI therapeutic efficacy, and summarizes recent strategies to improve drug tolerance and enhance anti-tumor effects by targeting T-cell metabolism alongside ICI therapy. The identification of potential targets for altering T-cell metabolism can significantly contribute to the development of methods to predict therapeutic responsiveness in patients receiving ICI therapy, which are currently unknown but would be of great clinical significance.
    Keywords:  T cell metabolism; immune checkpoint; immune checkpoints inhibitor; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.1046755
  9. Arthritis Rheumatol. 2022 Dec 27.
    Modulating T-bet-promoted energy metabolism in pathogenic age/autoimmune-associated B cells ameliorates lupus autoimmunity.
    Xiaxia Han, Shuangshuang Gu, Soon-Min Hong, Yang Jiang, Jinsong Zhang, Chao Yao, Zhihua Yin, Zhizhong Ye, Huihua Ding, Sheng Chen, Dai Dai, Nan Shen.
       OBJECTIVE: Emerging evidences indicate that a distinct CD11c+ T-bet+ B cell subset termed age/autoimmune-associated B cells (ABCs) is the major pathogenic autoantibody producer in lupus. Human lupus is associated with significant metabolic alterations, but how ABCs orchestrate their typical transcription factors (TFs) and metabolic programs to meet specific functional requirements is unclear. Our goal is to characterize the metabolism of ABCs and identify the regulators of metabolic pathways for developing new therapies for ABC-mediated autoimmunity.
    METHODS: We developed a T-bet-tdTomato reporter mouse strain to trace live T-bet+ B cells and adoptively transferred CD4+ T cells from Bm12 mice to induce lupus. Then CD11c+ tdTomato+ B cells were sorted and conducted RNA sequencing and extracellular flux assay. Metabolic restriction to constrain ABC formation was tested on human and mouse B cells. The metabolic intervention was conducted in the Bm12-induced lupus model.
    RESULTS: ABCs exhibited a hypermetabolic state with enhanced glycolytic capacity. The increased glycolytic rate in ABCs was promoted by IFN-γ signaling. T-bet, a downstream TF of IFN-γ, regulated the gene program of the glycolysis pathway in ABCs by repressing the expression of Bcl6. Functionally, glycolysis restriction could impair ABC formation. The engagement of glycolysis promoted survival and terminal differentiation of antibody-secreting cells. Administration of glycolysis inhibitor ameliorated ABCs accumulation and autoantibody production in Bm12-induced lupus model.
    CONCLUSION: T-bet can couple immune signals and metabolic programming to establish pathogenic ABC formation and functional capacities. Modulating ABC favored metabolic program could be a novel therapeutic approach for lupus. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/art.42433
  10. Front Immunol. 2022 ;13 1079642
    Fatty acid composition and metabolic partitioning of α-linolenic acid are contingent on life stage in human CD3+ T lymphocytes.
    Annette L West, Johanna von Gerichten, Nicola A Irvine, Elizabeth A Miles, Karen A Lillycrop, Philip C Calder, Barbara A Fielding, Graham C Burdge.
       Introduction: Immune function changes across the life course; the fetal immune system is characterised by tolerance while that of seniors is less able to respond effectively to antigens and is more pro-inflammatory than in younger adults. Lipids are involved centrally in immune function but there is limited information about how T cell lipid metabolism changes during the life course.
    Methods and Results: We investigated whether life stage alters fatty acid composition, lipid droplet content and α-linolenic acid (18:3ω-3) metabolism in human fetal CD3+ T lymphocytes and in CD3+ T lymphocytes from adults (median 41 years) and seniors (median 70 years). Quiescent fetal T cells had higher saturated (SFA), monounsaturated fatty acid (MUFA), and ω-6 polyunsaturated fatty acid (PUFA) contents than adults or seniors. Activation-induced changes in fatty acid composition differed between life stages. The principal metabolic fates of [13C]18:3ω-3 were constitutive hydroxyoctadecatrienoic acid synthesis and β-oxidation and carbon recycling into SFA and MUFA. These processes declined progressively across the life course. Longer chain ω-3 PUFA synthesis was a relatively minor metabolic fate of 18:3ω-3 at all life stages. Fetal and adult T lymphocytes had similar lipid droplet contents, which were lower than in T cells from seniors. Variation in the lipid droplet content of adult T cells accounted for 62% of the variation in mitogen-induced CD69 expression, but there was no significant relationship in fetal cells or lymphocytes from seniors.
    Discussion: Together these findings show that fatty acid metabolism in human T lymphocytes changes across the life course in a manner that may facilitate the adaptation of immune function to different life stages.
    Keywords:  CD69; T lymphocyte; essential fatty acid; fatty acid (composition); hydroxyoctadecadienoic acids; life course; lipid droplet; α-linolenic acid
    DOI:  https://doi.org/10.3389/fimmu.2022.1079642
  11. Front Immunol. 2022 ;13 1016670
    The role of metabolism on regulatory T cell development and its impact in tumor and transplantation immunity.
    Aleksey S Bulygin, Julia N Khantakova, Nadezhda S Shkaruba, Hiroshi Shiku, Sergey S Sennikov.
      Regulatory CD4+ T (Treg) cells play a key role in the induction of immune tolerance and in the prevention of autoimmune diseases. Treg cells are defined by the expression of transcription factor FOXP3, which ensures proliferation and induction of the suppressor activity of this cell population. In a tumor microenvironment, after transplantation or during autoimmune diseases, Treg cells can respond to various signals from their environment and this property ensures their suppressor function. Recent studies showed that a metabolic signaling pathway of Treg cells are essential in the control of Treg cell proliferation processes. This review presents the latest research highlights on how the influence of extracellular factors (e.g. nutrients, vitamins and metabolites) as well as intracellular metabolic signaling pathways regulate tissue specificity of Treg cells and heterogeneity of this cell population. Understanding the metabolic regulation of Treg cells should provide new insights into immune homeostasis and disorders along with important therapeutic implications for autoimmune diseases, cancer and other immune-system-mediated disorders.
    Keywords:  T cells; fatty acid oxidation; glycolysis; immunometabolism; transplant microenvironment; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2022.1016670
  12. Drug Deliv Transl Res. 2022 Dec 24.
    Short-chain fatty acid-mediated epigenetic modulation of inflammatory T cells in vitro.
    David A McBride, Nicholas C Dorn, Mina Yao, Wade T Johnson, Wei Wang, Nunzio Bottini, Nisarg J Shah.
      Short-chain fatty acids (SCFAs) are major metabolic products of indigestible polysaccharides in the gut and mediate the function of immune cells to facilitate homeostasis. The immunomodulatory effect of SCFAs has been attributed, at least in part, to the epigenetic modulation of immune cells through the inhibition the nucleus-resident enzyme histone deacetylase (HDAC). Among the downstream effects, SCFAs enhance regulatory T cells (Treg) over inflammatory T helper (Th) cells, including Th17 cells, which can be pathogenic. Here, we characterize the potential of two common SCFAs-butyrate and pentanoate-in modulating differentiation of T cells in vitro. We show that butyrate but not pentanoate exerts a concentration-dependent effect on Treg and Th17 differentiation. Increasing the concentration of butyrate suppresses the Th17-associated RORγtt and IL-17 and increases the expression of Treg-associated FoxP3. To effectively deliver butyrate, encapsulation of butyrate in a liposomal carrier, termed BLIPs, reduced cytotoxicity while maintaining the immunomodulatory effect on T cells. Consistent with these results, butyrate and BLIPs inhibit HDAC and promote a unique chromatin landscape in T cells under conditions that otherwise promote conversion into a pro-inflammatory phenotype. Motif enrichment analysis revealed that butyrate and BLIP-mediated suppression of Th17-associated chromatin accessibility corresponded with a marked decrease in bZIP family transcription factor binding sites. These results support the utility and further evaluation of BLIPs as an immunomodulatory agent for autoimmune disorders that are characterized by chronic inflammation and pathogenic inflammatory T cells.
    Keywords:  Epigenetic modulation; Immunomodulation; Short-chain fatty acids; T cells
    DOI:  https://doi.org/10.1007/s13346-022-01284-6
  13. Cell Rep. 2022 Dec 27. pii: S2211-1247(22)01796-X. [Epub ahead of print]41(13): 111897
    Pyruvate kinase M2 mediates IL-17 signaling in keratinocytes driving psoriatic skin inflammation.
    Flávio P Veras, Gabriel A Publio, Bruno M Melo, Douglas S Prado, Thainá Norbiato, Nerry T Cecilio, Carlos Hiroki, Luis Eduardo A Damasceno, Rebecca Jung, Juliana E Toller-Kawahisa, Timna V Martins, Stella F Assunção, Diogenes Lima, Marcia G Alves, Gabriel V Vieira, Lucas A Tavares, Ana L R Alves-Rezende, Susanne H Karbach, Helder I Nakaya, Thiago M Cunha, Cacilda S Souza, Fernando Q Cunha, Katiuchia U Sales, Ari Waisman, José C Alves-Filho.
      Psoriasis is an inflammatory skin disease characterized by keratinocyte proliferation and inflammatory cell infiltration induced by IL-17. However, the molecular mechanism through which IL-17 signaling in keratinocytes triggers skin inflammation remains not fully understood. Pyruvate kinase M2 (PKM2), a glycolytic enzyme, has been shown to have non-metabolic functions. Here, we report that PKM2 mediates IL-17A signaling in keratinocytes triggering skin psoriatic inflammation. We find high expression of PKM2 in the epidermis of psoriatic patients and mice undergoing psoriasis models. Specific depletion of PKM2 in keratinocytes attenuates the development of experimental psoriasis by reducing the production of pro-inflammatory mediators. Mechanistically, PKM2 forms a complex with Act1 and TRAF6 regulating NF-κB transcriptional signaling downstream of the IL-17 receptor. As IL-17 also induces PKM2 expression in keratinocytes, our findings reveal a sustained signaling circuit critical for the psoriasis-driving effects of IL-17A, suggesting that PKM2 is a potential therapeutic target for psoriasis.
    Keywords:  Act1; CP: Immunology; IL-17A; NF-κB; PKM2; TRAF6; inflammation; keratinocyte; psoriasis; skin
    DOI:  https://doi.org/10.1016/j.celrep.2022.111897
  14. Front Immunol. 2022 ;13 1103379
    Editorial: Lactate metabolism and regulation of the immune response.
    Marcela Hortová-Kohoutková, János G Filep, Jan Frič.
      
    Keywords:  immune cell; immunometabolism; immunoregulation; inflammation; lactate
    DOI:  https://doi.org/10.3389/fimmu.2022.1103379
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