Trained immunity amplifies intestinal complement 3 to maintain Th17 cells against bacterial infection-induced enteritis in zebrafish
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ABSTRACT:
PROVIDER: PRJNA1204310 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31852177_1.fastq.gz | Fastqsanger.gz | |||
| SRR31852177_2.fastq.gz | Fastqsanger.gz | |||
| SRR31852178_1.fastq.gz | Fastqsanger.gz | |||
| SRR31852178_2.fastq.gz | Fastqsanger.gz | |||
| SRR31852179_1.fastq.gz | Fastqsanger.gz |
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Project description:Infectious enteritis is often accompanied with immuno-disorder of intestinal immune cells caused by microbials infection. Trained immunity is classically characterized by long-term functional reprogramming of innate immune cells to combat infectious diseases. However, whether the induction of trained immunity plays a role in protecting infectious enteritis remains largely unknown. Here, through establishing an in vivo β-glucan training and E. piscicida infection model in zebrafish, we observe that induction of trained immunity could alleviate bacterial infection-caused enteritis. Moreover, we identify intestinal complement C3 as a crucial target of trained immunity and could be amplified in response to bacterial infection. Furthermore, we reveal that trained immunity could reverse the reduction of intestinal Th17 cells in C3-dependent manner to alleviate infectious enteritis. Taken together, our results uncover the role of complement C3-mediated trained immunity in maintaining Th17 cells and intestine homeostasis, and provide a theoretical strategy for immunotherapies of infectious enteritis.
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Project description:A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn and celiac disease in humans. We show that mice expressing point mutations in A20’s M1-ubiquitin binding zinc-finger 7 (ZF7) domain spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with normal luminal flora drives duodenal IL-22 expression and duodenitis. A20ZF7 TH17/22 cells autonomously express more RORgammat and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7 T cells. Acute inhibition of RORgammat normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORgammat expression and IL22 transcription. These studies link A20’s M1-ubiquitin binding function with RORgammat expression, expansion of TH17/22 cells, and epigenetic activation of IL-22 driven enteritis.
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Project description:A20, encoded by the TNFAIP3 gene, is a protein linked to Crohn and celiac disease in humans. We show that mice expressing point mutations in A20’s M1-ubiquitin binding zinc-finger 7 (ZF7) domain spontaneously develop proximal enteritis that requires both luminal microbes and T cells. Cellular and transcriptomic profiling reveal expansion of TH17/22 cells and exuberant expression of IL-17A and IL-22 in intestinal lamina propria of A20ZF7 mice. While deletion of IL-17A from A20ZF7 mice exacerbates enteritis, deletion of IL-22 abrogates intestinal epithelial cell hyperproliferation, barrier dysfunction, and alarmin expression. Colonization of adult germ-free mice with normal luminal flora drives duodenal IL-22 expression and duodenitis. A20ZF7 TH17/22 cells autonomously express more RORgammat and IL-22 after differentiation in vitro. ATAC sequencing identified an enhancer region upstream of the Il22 gene, and this enhancer demonstrated increased activating histone acetylation coupled with exaggerated Il22 transcription in A20ZF7 T cells. Acute inhibition of RORgammat normalized histone acetylation at this enhancer. Finally, CRISPR/Cas9-mediated ablation of A20ZF7 in human T cells increases RORgammat expression and IL22 transcription. These studies link A20’s M1-ubiquitin binding function with RORgammat expression, expansion of TH17/22 cells, and epigenetic activation of IL-22 driven enteritis.
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Project description:Complement protein C3 is crucial for immune responses in mucosal sites like the respiratory system, where it aids in microbe elimination and enhances inflammation. While trained immunity – enhanced secondary responses of innate immune cells after prior exposure – is well-studied, the role of the complement system in trained immune responses remains unclear. We investigated the role of C3 in trained immunity and found that in vivo, trained wild-type mice showed significantly elevated pro-inflammatory cytokines and increased C3a levels upon a second stimulus, whereas C3-deficient mice exhibited a blunted cytokine response and heightened evidence of lung injury. Ex vivo, C3-deficient alveolar macrophages (AMs) displayed reduced chemokine and cytokine output after training, which was restored by exogenous C3 but not by C3a. Inhibiting C3aR, both pharmacologically and with a genetic C3aR knockout, prevented this restoration, indicating the necessity of C3aR engagement. Mechanistically, trained WT AMs demonstrated enhanced glycolytic activity compared to C3-deficient AMs – a defect corrected by exogenous C3 in a C3aR-dependent manner. These findings reveal that C3 modulates trained immunity in AMs through C3aR signaling, affecting cytokine production and metabolic reprogramming, and highlight a novel role for C3 in trained immunity.
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Project description:We have shown that cathelicidin amplifies Th17 differentiation. To determine the mechanism through which this host defence peptide acts, we performed multiplex gene expression analysis (NanoString) to identify the effects of mouse cathelicidin (mCRAMP) on murine CD4+ T cells cultured under Th17-driving conditions.
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Project description:T helper cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here we demonstrate that high NaCl conditions induced a stable, pathogen-specific, anti-inflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and interleukin (IL)-17-expression in high-NaCl conditions. The NaCl-induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a pro-inflammatory and TGF--low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.
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Project description:Interleukin 17 (IL-17) producing T helper 17 (Th17) cells are critical drivers of pathogenesis in a variety of autoimmune and inflammatory diseases. Strategies to mitigate excessive Th17 response thus remain an attractive target for immunotherapies. Here we report that Cancerous Inhibitor of Protein Phosphatase 2A (CIP2A) regulates IL-17 production by Th17 cells in human and mouse. Using CIP2A knock-out (KO) mice and siRNA-mediated CIP2A silencing in human primary CD4+ T cells, we demonstrated that CIP2A silencing results in a significant increase in IL-17 production. Interestingly, CIP2A deficient Th17 cells were characterized by increased strength and duration of STAT3 (Y705) phosphorylation. Genome-wide gene expression profile as well as the p-STAT3 (Y705) interactome of CIP2A deficient Th17 cells identified that CIP2A regulates the strength of the interaction between Acylglycerol kinase (AGK) and STAT3, and thereby, modulates STAT3 phosphorylation as well as expression of IL-17 in Th17 cells. Our results uncover the physiological function of CIP2A in Th17 cells and provides new opportunities for therapeutic intervention in Th17 cell mediated diseases.
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