bims-traimu Biomed News
on Trained immunity
Issue of 2024–09–15
fiveteen papers selected by
Yantong Wan, Southern Medical University
  1. Early transcriptomic response of innate immune cells to subcutaneous BCG vaccination of mice.
  2. Complement C5a Receptor Signaling in Macrophages Enhances Trained Immunity Through mTOR Pathway Activation.
  3. Methylation and transcriptomic profiling reveals short term and long term regulatory responses in polarized macrophages.
  4. Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice.
  5. An anti-aging vaccine: BCG turns back the clock on remyelination failure.
  6. Neighbor's feedback helps macrophages learn tolerance in the gut.
  7. HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis.
  8. Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.
  9. Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.
  10. Vangl2 suppresses NF-κB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation.
  11. A second-generation recombinant BCG strain combines protection against murine tuberculosis with an enhanced safety profile in immunocompromised hosts.
  12. Promoter DNA methylation and transcription factor condensation are linked to transcriptional memory in mammalian cells.
  13. A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.
  14. Sex differences in the transcriptional response to acute inflammatory challenge: A randomized controlled trial of endotoxin.
  15. Gasdermin D-mediated metabolic crosstalk promotes tissue repair.
  1. BMC Res Notes. 2024 Sep 09. 17(1): 253
    Early transcriptomic response of innate immune cells to subcutaneous BCG vaccination of mice.
    Liya Kondratyeva, Alexey Kuzmich, Irina Linge, Victor Pleshkan, Olga Rakitina, Sofia Kondratieva, Eugene Snezhkov, Alexander Sass, Irina Alekseenko.
       OBJECTIVES: Current data suggests that Bacille Calmette-Guerin (BCG) vaccination contributes to nonspecific enhancement of resistance to various infections. Thus, BCG vaccination induces both specific immunity against mycobacteria and non-specific "trained immunity" against various pathogens. To understand the fundamental mechanisms of "trained" immunity, studies of transcriptome changes occurring during BCG vaccination in innate immunity cells, as well as in their precursors, are necessary. Furthermore, this data possesses important significance for practical applications associated with the development of recombinant BCG strains aimed to enhance innate immunity against diverse infectious agents.
    DATA DESCRIPTION: We performed RNA sequencing of innate immune cells derived from murine bone marrow and spleen three days after subcutaneous BCG vaccination. Using fluorescence-activated cell sorting we obtained three cell populations for each mouse from both control and BCG vaccinated groups: bone marrow monocytes and neutrophils and splenic NK-cells. Then double-indexed cDNA libraries for Illumina sequencing from the collected samples were prepared, the resulting cDNA library mix was subjected to NovaSeq 6000 sequencing. This paper describes the collection of 24 RNA sequencing samples comprising 4 sets of immune cell populations obtained from subcutaneously BCG-vaccinated and control mice.
    Keywords:  BCG; C57BL; Immune cells; Innate immunity; RNA-seq; Trained immunity; Transcriptomes; Vaccination
    DOI:  https://doi.org/10.1186/s13104-024-06901-w
  2. Immune Netw. 2024 Aug;24(4): e24
    Complement C5a Receptor Signaling in Macrophages Enhances Trained Immunity Through mTOR Pathway Activation.
    Eun-Hyeon Shim, Sae-Hae Kim, Doo-Jin Kim, Yong-Suk Jang.
      Complement C5a receptor (C5aR) signaling in immune cells has various functions, inducing inflammatory or anti-inflammatory responses based on the type of ligand present. The Co1 peptide (SFHQLPARSRPLP) has been reported to activate C5aR signaling in dendritic cells. We investigated the effect of C5aR signaling via the Co1 peptide on macrophages. In peritoneal macrophages, the interaction between C5aR and the Co1 peptide activated the mTOR pathway, resulting in the production of pro-inflammatory cytokines. Considering the close associations of mTOR signaling with IL-6 and TNF-α in macrophage training, our findings indicate that the Co1 peptide amplifies β-glucan-induced trained immunity. Overall, this research highlights a previously underappreciated aspect of C5aR signaling in trained immunity, and posits that the Co1 peptide is a potentially effective immunomodulator for enhancing trained immunity.
    Keywords:  Adjuvants, immunogenic; C5a receptor; Immunomodulator; Inflammation; Trained immunity
    DOI:  https://doi.org/10.4110/in.2024.24.e24
  3. Comput Struct Biotechnol J. 2024 Dec;25 143-152
    Methylation and transcriptomic profiling reveals short term and long term regulatory responses in polarized macrophages.
    Giorgia Migliaccio, Jack Morikka, Giusy Del Giudice, Maaret Vaani, Lena Möbus, Angela Serra, Antonio Federico, Dario Greco.
      Macrophage plasticity allows the adoption of distinct functional states in response to environmental cues. While unique transcriptomic profiles define these states, focusing solely on transcription neglects potential long-term effects. The investigation of epigenetic changes can be used to understand how temporary stimuli can result in lasting effects. Epigenetic alterations play an important role in the pathophysiology of macrophages, including their trained innate immunity, enabling faster and more efficient inflammatory responses upon subsequent encounters to the same pathogen or insult. In this study, we used a multi-omics approach to elucidate the interplay between gene expression and DNA-methylation, to explore the potential long-term effects of diverse polarizing environments on macrophage activity. We identified a common core set of genes that are differentially methylated regardless of exposure type, indicating a potential common fundamental mechanism for adaptation to various stimuli. Functional analysis revealed that processes requiring rapid responses displayed transcriptomic regulation, whereas functions critical for long-term adaptations exhibited co-regulation at both transcriptomic and epigenetic levels. Our study uncovers a novel set of genes linked to the long-term effects of macrophage polarization. This discovery underscores the potential of epigenetics in elucidating how macrophages establish long-term memory and influence health outcomes.
    Keywords:  Epigenetics; Long-term effect; Macrophage plasticity; Multi-omics; Trained immunity
    DOI:  https://doi.org/10.1016/j.csbj.2024.08.018
  4. EMBO Mol Med. 2024 Sep 11.
    Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice.
    Deyan Chen, Jing Wu, Fang Zhang, Ruining Lyu, Qiao You, Yajie Qian, Yurong Cai, Xiaoyan Tian, Hongji Tao, Yating He, Waqas Nawaz, Zhiwei Wu.
      Innate immune cells have been acknowledged as trainable in recent years. While intestinal tuft cells are recognized for their crucial roles in the host defense against intestinal pathogens, there remains uncertainty regarding their trainability. Enterovirus 71 (EV71), a prevalent enterovirus that primarily infects children but rarely infects adults. At present, there is a significant expansion of intestinal tuft cells in the EV71-infected mouse model, which is associated with EV71-induced interleukin-25 (IL-25) production. Further, we found that IL-25 pre-treatment at 2 weeks old mouse enabled tuft cells to acquire immune memory. This was evidenced by the rapid expansion and stronger response of IL-25-trained tuft cells in response to EV71 infection at 6 weeks old, surpassing the reactivity of naïve tuft cells in mice without IL-25-trained progress. Interestingly, IL-25-trained intestinal tuft cells exhibit anti-enteroviral effect via producing a higher level of IL-25. Mechanically, IL-25 treatment upregulates spermidine/spermine acetyl-transferase enzyme (SAT1) expression, mediates intracellular polyamine deficiency, further inhibits enterovirus replication. In summary, tuft cells can be trained by IL-25, which supports faster and higher level IL-25 production in response to EV71 infection and further exhibits anti-enteroviral effect via SAT1-mediated intracellular polyamine deficiency. Given that IL-25 can be induced by multiple gut microbes during human growth and development, including shifts in gut flora abundance, which may partially explain the different susceptibility to enteroviral infections between adults and children.
    Keywords:  Anti-Enteroviral Response; IL-25; SAT1; Trained Immunity; Tuft Cells
    DOI:  https://doi.org/10.1038/s44321-024-00128-9
  5. Immunity. 2024 Sep 10. pii: S1074-7613(24)00374-1. [Epub ahead of print]57(9): 2005-2007
    An anti-aging vaccine: BCG turns back the clock on remyelination failure.
    Janssen M Kotah, Bart J L Eggen.
      Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.001
  6. Immunity. 2024 Sep 10. pii: S1074-7613(24)00411-4. [Epub ahead of print]57(9): 2002-2004
    Neighbor's feedback helps macrophages learn tolerance in the gut.
    Giuseppe Giuliani, Jayajit Das.
      Intestinal macrophages play a key role in regulating immune tolerance in the gut. In this issue of Immunity, Mertens et al. uncover a mechanism for the establishment of memory in macrophage tolerance in the gut involving a bistable metabolic switch in macrophages and an intercellular positive feedback between macrophages and intestinal epithelial cells (IECs).
    DOI:  https://doi.org/10.1016/j.immuni.2024.08.012
  7. Sci Transl Med. 2024 Sep 11. 16(764): eadi0284
    HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis.
    Ishtiaq Jeelani, Jae-Su Moon, Flavia Franco da Cunha, Chanond A Nasamran, Seokhyun Jeon, Xinhang Zhang, Gautam K Bandyopadhyay, Katarzyna Dobaczewska, Zbigniew Mikulski, Mojgan Hosseini, Xiao Liu, Tatiana Kisseleva, David A Brenner, Seema Singh, Rohit Loomba, Minkyu Kim, Yun Sok Lee.
      Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement of KCs with bone marrow-derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that hypoxia-inducible factor 2α (HIF-2α) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2α stimulated mammalian target of rapamycin (mTOR)- and extracellular signal-regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2α-dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2α promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage-specific or KC-specific HIF-2α depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2α-specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype-specific effects of HIF-2α collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH.
    DOI:  https://doi.org/10.1126/scitranslmed.adi0284
  8. Nat Metab. 2024 Sep 06.
    Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.
    Santosh R Sukka, Patrick B Ampomah, Lancia N F Darville, David Ngai, Xiaobo Wang, George Kuriakose, Yuling Xiao, Jinjun Shi, John M Koomen, Robert H McCusker, Ira Tabas.
      Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.
    DOI:  https://doi.org/10.1038/s42255-024-01115-7
  9. Cell. 2024 Sep 02. pii: S0092-8674(24)00898-5. [Epub ahead of print]
    Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.
    Pietro Fontana, Gang Du, Ying Zhang, Haiwei Zhang, Setu M Vora, Jun Jacob Hu, Ming Shi, Ahmet B Tufan, Liam B Healy, Shiyu Xia, Dian-Jang Lee, Zhouyihan Li, Pilar Baldominos, Heng Ru, Hongbo R Luo, Judith Agudo, Judy Lieberman, Hao Wu.
      Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.
    Keywords:  GSDMD; GSDMD agonist; antitumor immunity; cancer; checkpoint blockade; gasdermin; immunogenic cell death; immunotherapy; pyroptosis; tumor
    DOI:  https://doi.org/10.1016/j.cell.2024.08.007
  10. Elife. 2024 Sep 13. pii: RP87935. [Epub ahead of print]12
    Vangl2 suppresses NF-κB signaling and ameliorates sepsis by targeting p65 for NDP52-mediated autophagic degradation.
    Jiansen Lu, Jiahuan Zhang, Huaji Jiang, Zhiqiang Hu, Yufen Zhang, Lian He, Jianwu Yang, Yingchao Xie, Dan Wu, Hongyu Li, Ke Zeng, Peng Tan, Qingyue Xiao, Zijing Song, Chenglong Pan, Xiaochun Bai, Xiao Yu.
      Van Gogh-like 2 (Vangl2), a core planar cell polarity component, plays an important role in polarized cellular and tissue morphology induction, growth development, and cancer. However, its role in regulating inflammatory responses remains elusive. Here, we report that Vangl2 is upregulated in patients with sepsis and identify Vangl2 as a negative regulator of The nuclear factor-kappaB (NF-κB) signaling by regulating the protein stability and activation of the core transcription component p65. Mice with myeloid-specific deletion of Vangl2 (Vangl2ΔM) are hypersusceptible to lipopolysaccharide (LPS)-induced septic shock. Vangl2-deficient myeloid cells exhibit enhanced phosphorylation and expression of p65, therefore, promoting the secretion of proinflammatory cytokines after LPS stimulation. Mechanistically, NF-κB signaling-induced-Vangl2 recruits E3 ubiquitin ligase PDLIM2 to catalyze K63-linked ubiquitination on p65, which serves as a recognition signal for cargo receptor NDP52-mediated selective autophagic degradation. Taken together, these findings demonstrate Vangl2 as a suppressor of NF-κB-mediated inflammation and provide insights into the crosstalk between autophagy and inflammatory diseases.
    Keywords:  NF-κB signaling; PDLIM2; Vangl2; human; immunology; inflammation; mouse; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.7554/eLife.87935
  11. Vaccine. 2024 Oct 24. pii: S0264-410X(24)00973-3. [Epub ahead of print]42(24): 126291
    A second-generation recombinant BCG strain combines protection against murine tuberculosis with an enhanced safety profile in immunocompromised hosts.
    Ana Maria Valencia-Hernandez, Guangzu Zhao, Socorro Miranda-Hernandez, Cristian Alfredo Segura-Cerda, Cesar Pedroza-Roldan, Julia Seifert, Michel de Jesus Aceves-Sanchez, Mirna Burciaga-Flores, Abel Gutierrez-Ortega, Lidia Del Pozo-Ramos, Mario Alberto Flores-Valdez, Andreas Kupz.
      Bacille Calmette-Guérin (BCG) remains the only licensed vaccine against tuberculosis (TB). While BCG protects against TB in children, its protection against pulmonary TB in adults is suboptimal, and the development of a better TB vaccine is a global health priority. Previously, we reported two recombinant BCG strains effective against murine TB with low virulence and lung pathology in immunocompromised mice and guinea pigs. We have recently combined these two recombinant BCG strains into one novel vaccine candidate (BCGΔBCG1419c::ESAT6-PE25SS) and evaluated its immunogenicity, efficacy and safety profile in mice. This new vaccine candidate is non-inferior to BCG in protection against TB, presents reduced pro-inflammatory immune responses and displays an enhanced safety profile.
    Keywords:  Immunocompromised mice; Recombinant BCG; Tuberculosis; Vaccine development
    DOI:  https://doi.org/10.1016/j.vaccine.2024.126291
  12. Cell Syst. 2024 Sep 04. pii: S2405-4712(24)00237-0. [Epub ahead of print]
    Promoter DNA methylation and transcription factor condensation are linked to transcriptional memory in mammalian cells.
    Shenqi Fan, Liang Ma, Chengzhi Song, Xu Han, Bijunyao Zhong, Yihan Lin.
      The regulation of genes can be mathematically described by input-output functions that are typically assumed to be time invariant. This fundamental assumption underpins the design of synthetic gene circuits and the quantitative understanding of natural gene regulatory networks. Here, we found that this assumption is challenged in mammalian cells. We observed that a synthetic reporter gene can exhibit unexpected transcriptional memory, leading to a shift in the dose-response curve upon a second induction. Mechanistically, we investigated the cis-dependency of transcriptional memory, revealing the necessity of promoter DNA methylation in establishing memory. Furthermore, we showed that the synthetic transcription factor's effective DNA binding affinity underlies trans-dependency, which is associated with its capacity to undergo biomolecular condensation. These principles enabled modulating memory by perturbing either cis- or trans-regulation of genes. Together, our findings suggest the potential pervasiveness of transcriptional memory and implicate the need to model mammalian gene regulation with time-varying input-output functions. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  CpG methylation; biomolecular condensation; gene regulation; input-output function; massively parallel reporter assay; synthetic biology; transcriptional memory
    DOI:  https://doi.org/10.1016/j.cels.2024.08.007
  13. EMBO Mol Med. 2024 Sep 11.
    A critical role for HNF4α in polymicrobial sepsis-associated metabolic reprogramming and death.
    Céline Van Dender, Steven Timmermans, Ville Paakinaho, Tineke Vanderhaeghen, Jolien Vandewalle, Maarten Claes, Bruno Garcia, Bart Roman, Jan De Waele, Siska Croubels, Karolien De Bosscher, Philip Meuleman, Antoine Herpain, Jorma J Palvimo, Claude Libert.
      In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.
    Keywords:  Acute Phase Response Failure; HNF4α Dysfunction; Liver; PPARα-mediated Lipid Dysfunction; Sepsis
    DOI:  https://doi.org/10.1038/s44321-024-00130-1
  14. Brain Behav Immun Health. 2024 Oct;40 100840
    Sex differences in the transcriptional response to acute inflammatory challenge: A randomized controlled trial of endotoxin.
    Chloe C Boyle, Steve W Cole, Naomi I Eisenberger, Richard Olmstead, Elizabeth C Breen, Michael R Irwin.
       Background: Sex differences in immune-based disorders are well-established, with female sex associated with a markedly heightened risk of autoimmune disease. Female sex is also overrepresented in other conditions associated with elevated inflammation, including depression, chronic pain, and chronic fatigue. The mechanisms underlying these disparities are unclear. This study used an experimental model of inflammatory challenge to interrogate molecular mechanisms that may contribute to female vulnerability to disorders with an inflammatory basis.
    Method: In this analysis of a secondary outcome from a randomized controlled trial, 111 participants (67 female) received either a bolus injection of endotoxin (n = 59) or placebo (n = 52). Participants provided blood samples before and 0.5 h post-injection for assessment of differential activation of key pro-inflammatory (i.e., activator protein (AP)-1; nuclear factor (NF)-κB) and immunoregulatory (i.e., glucocorticoid receptor (GR); cAMP response element binding protein (CREB)) signaling pathways via genome-wide expression profiling and promoter-based bioinformatics analyses.
    Results: Relative to males, females exhibited greater endotoxin-induced increases in bioinformatic measures of CREB transcription factor activity (p's < 0.01). However, contrary to hypotheses, female vs. male sex was not associated with greater increases in activation of NF-κB, AP-1, or GR in response to endotoxin vs. placebo administration.
    Conclusions: This work suggests CREB signaling as a critical upstream biological pathway that should be further interrogated as a mechanism of female vulnerability to immune-related disorders. Future work should clarify whether increased CREB signaling indicates sex differences in activity of the sympathetic nervous system or other physiological pathways that signal through CREB, such as prostaglandin release.
    Keywords:  Gene expression; Immune system; Inflammation; Sex; Transcription factors
    DOI:  https://doi.org/10.1016/j.bbih.2024.100840
  15. Nature. 2024 Sep 11.
    Gasdermin D-mediated metabolic crosstalk promotes tissue repair.
    Zhexu Chi, Sheng Chen, Dehang Yang, Wenyu Cui, Yang Lu, Zhen Wang, Mobai Li, Weiwei Yu, Jian Zhang, Yu Jiang, Ruya Sun, Qianzhou Yu, Tianyi Hu, Xiaoyang Lu, Qiqi Deng, Yidong Yang, Tianming Zhao, Mengfei Chang, Yuying Li, Xue Zhang, Min Shang, Qian Xiao, Kefeng Ding, Di Wang.
      The establishment of an early pro-regenerative niche is crucial for tissue regeneration1,2. Gasdermin D (GSDMD)-dependent pyroptosis accounts for the release of inflammatory cytokines upon various insults3-5. However, little is known about its role in tissue regeneration followed by homeostatic maintenance. Here, we show that macrophage GSDMD deficiency delayed tissue recovery, with little impact on the local inflammatory milieu or the lytic pyroptosis process. Metabolite secretome profiling of hyperactivated macrophages unveiled the non-canonical metabolite-secreting function of GSDMD. And we further identified 11,12-epoxyeicosatrienoic acid (11,12-EET) as a bioactive pro-healing oxylipin, secreted from hyperactive macrophages in a GSDMD-dependent manner. Indeed, accumulation of 11,12-EET by direct supplementation or deletion of its hydrolytic enzyme Ephx2 accelerated muscle regeneration. We further demonstrated that the Ephx2 level accumulated within aged muscle. And consecutive 11,12-EET treatment rejuvenated aged muscle. Mechanistically, 11,12-EET amplifies FGF-FGFR signaling by modulating FGF liquid-liquid phase separation, hence boosting the activation and proliferation of muscle stem cells (MuSCs). These data depict a GSDMD-guided metabolite crosstalk between macrophages and MuSCs that governs the repair process, which offers new therapeutic insights for the regeneration of injured or aged tissues.
    DOI:  https://doi.org/10.1038/s41586-024-08022-7
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:29.