查看更多>>摘要：Mannose is a naturally occurring sugar widely consumed in the daily diet;however,mechanistic insights into how mannose metabolism affects intestinal inflammation remain lacking.Herein,we reported that mannose supplementation ameliorated colitis development and promoted colitis recovery.Macrophage-secreted inflammatory cytokines,particularly TNF-α,induced pathological endoplasmic reticulum stress(ERS)in intestinal epithelial cells(IECs),which was prevented by mannose via normalization of protein N-glycosylation.By preserving epithelial integrity,mannose reduced the inflammatory activation of colonic macrophages.On the other hand,mannose directly suppressed macrophage TNF-α production translationally by reducing the glyceraldehyde 3-phosphate level,thus promoting GAPDH binding to TNF-α mRNA.Additionally,we found dysregulated mannose metabolism in the colonic mucosa of patients with inflammatory bowel disease.Finally,we revealed that activating PMM2 activity with epalrestat,a clinically approved drug for the treatment of diabetic neuropathy,elicited further sensitization to the therapeutic effect of mannose.Therefore,mannose metabolism prevents TNF-α-mediated pathogenic crosstalk between IECs and intestinal macrophages,thereby normalizing aberrant immunometabolism in the gut.
Chia George HsuWenjia LiMark SowdenCamila Lage Chávez...
131-142页
查看更多>>摘要：Polyribonucleotide nucleotidyltransferase 1(Pnpt1)plays critical roles in mitochondrial homeostasis by controlling mitochondrial RNA(mt-RNA)processing,trafficking and degradation.Pnpt1 deficiency results in mitochondrial dysfunction that triggers a type I interferon response,suggesting a role in inflammation.However,the role of Pnpt1 in inflammasome activation remains largely unknown.In this study,we generated myeloid-specific Pnpt1-knockout mice and demonstrated that Pnpt1 depletion enhanced interleukin-1 beta(IL-1β)and interleukin-18(IL-18)secretion in a mouse sepsis model.Using cultured peritoneal and bone marrow-derived macrophages,we demonstrated that Pnpt1 regulated NLRP3 inflammasome-dependent IL-1β release in response to lipopolysaccharide(LPS),followed by nigericin,ATP or poly(I:C)treatment.Pnpt1 deficiency in macrophages increased glycolysis after LPS administration and mt-reactive oxygen species(mt-ROS)after NLRP3 inflammasome activation.Pnpt1 activation of the inflammasome was dependent on increased glycolysis and the expression of mitochondrial antiviral-signaling protein(MAVS)but not NF-κB signaling.Collectively,these data suggest that Pnpt1 is an important mediator of inflammation,as shown by activation of the NLRP3 inflammasome in murine sepsis and cultured macrophages.
查看更多>>摘要：Due to their broad functional plasticity,myeloid cells contribute to both liver injury and recovery during acetaminophen overdose-induced acute liver injury(APAP-ALI).A comprehensive understanding of cellular diversity and intercellular crosstalk is essential to elucidate the mechanisms and to develop therapeutic strategies for APAP-ALI treatment.Here,we identified the function of IFN-I in the myeloid compartment during APAP-ALI.Utilizing single-cell RNA sequencing,we characterized the cellular atlas and dynamic progression of liver CD11b+cells post APAP-ALI in WT and STAT2 T403A mice,which was further validated by immunofluorescence staining,bulk RNA-seq,and functional experiments in vitro and in vivo.We identified IFN-I-dependent transcriptional programs in a three-way communication pathway that involved IFN-I synthesis in intermediate restorative macrophages,leading to CSF-1 production in aging neutrophils that ultimately enabled Trem2+ restorative macrophage maturation,contributing to efficient liver repair.Overall,we uncovered the heterogeneity of hepatic myeloid cells in APAP-ALI at single-cell resolution and the therapeutic potential of IFN-I in the treatment of APAP-ALI.
查看更多>>摘要：Dysregulation of gut homeostasis is associated with irritable bowel syndrome(IBS),a chronic functional gastrointestinal disorder affecting approximately 11.2%of the global population.The poorly understood pathogenesis of IBS has impeded its treatment.Here,we report that the E3 ubiquitin ligase tripartite motif-containing 27(TRIM27)is weakly expressed in IBS but highly expressed in inflammatory bowel disease(IBD),a frequent chronic organic gastrointestinal disorder.Accordingly,knockout of Trim27 in mice causes spontaneously occurring IBS-like symptoms,including increased visceral hyperalgesia and abnormal stool features,as observed in IBS patients.Mechanistically,TRIM27 stabilizes β-catenin and thus activates Wnt/β-catenin signaling to promote intestinal stem cell(ISC)self-renewal.Consistent with these findings,Trim27 deficiency disrupts organoid formation,which is rescued by reintroducing TRIM27 or β-catenin.Furthermore,Wnt/β-catenin signaling activator treatment ameliorates IBS symptoms by promoting ISC self-renewal.Taken together,these data indicate that TRIM27 is critical for maintaining gut homeostasis,suggesting that targeting the TRIM27/Wnt/β-catenin axis could be a potential treatment strategy for IBS.Our study also indicates that TRIM27 might serve as a potential biomarker for differentiating IBS from IBD.
查看更多>>摘要：Upon viral infection,cytoplasmic pattern recognition receptors detect viral nucleic acids and activate the adaptor protein VISA/MAVS-or MITA/STING-mediated innate antiviral response.Whether and how the innate antiviral response is regulated by neuronal endocrine functions is unclear.Here,we show that viral infection reduced the serum levels of the β-adrenergic hormones epinephrine and norepinephrine as well as the cellular levels of their receptors ADRB1 and ADRB2.We further show that an increase in epinephrine/norepinephrine level inhibited the innate antiviral response in an ADRB1-/2-dependent manner.Mechanistically,epinephrine/norepinephrine stimulation activated the downstream kinase PKA,which catalyzed the phosphorylation of MITA at S241,S243 and T263,inhibiting MITA activation and suppressing the innate immune response to DNA virus.In addition,phosphorylation of VISA at T54 by PKA antagonized the innate immune response to RNA virus.These findings reveal the regulatory mechanisms of innate antiviral responses by epinephrine/norepinephrine and provide a possible explanation for increased host susceptibility to viral infection in stressful and anxiety-promoting situations.
查看更多>>摘要：CD82 is a transmembrane protein that is involved in cancer suppression and activates immune cells;however,information on the NLRP3 inflammasome is limited.Herein,we show that although CD82 suppressed the activation of the NLRP3 inflammasome in vivo and in vitro,CD82 deficiency decreased the severity of colitis in mice.Furthermore,two binding partners of CD82,NLRP3 and BRCC3,were identified.CD82 binding to these partners increased the degradation of NLRP3 by blocking BRCC3-dependent K63-specific deubiquitination.Previous studies have shown that CD82-specific bacteria in the colon microbiota called Bacteroides vulgatus(B.vulgatus)regulated the expression of CD82 and promoted the activation of the NLRP3 inflammasome.Accordingly,we observed that B.vulgatus administration increased mouse survival by mediating CD82 expression and activating NLRP3 in mice with colitis.Overall,this study showed that CD82 suppression reduced the pathogenesis of colitis by elevating the activation of the NLRP3 inflammasome through BRCC3-dependent K63 deubiquitination.Based on our findings,we propose that B.vulgatus is a novel therapeutic candidate for colitis.
Ana Jordan-PaizGlòria MartrusFenja L.SteinertMax Kaufmann...
201-213页
查看更多>>摘要：Gastrointestinal infections are a major cause for serious clinical complications in infants.The induction of antibody responses by B cells is critical for protective immunity against infections and requires CXCR5+PD-1++ CD4+ T cells(TFH cells).We investigated the ontogeny of CXCR5+PD-1++ CD4+ T cells in human intestines.While CXCR5+PD-1++ CD4+ T cells were absent in fetal intestines,CXCR5+PD-1++ CD4+ T cells increased after birth and were abundant in infant intestines,resulting in significant higher numbers compared to adults.These findings were supported by scRNAseq analyses,showing increased frequencies of CD4+ T cells with a TFH gene signature in infant intestines compared to blood.Co-cultures of autologous infant intestinal CXCR5+PD-1+/-CD4+ T cells with B cells further demonstrated that infant intestinal TFH cells were able to effectively promote class switching and antibody production by B cells.Taken together,we demonstrate that functional TFH cells are numerous in infant intestines,making them a promising target for oral pediatric vaccine strategies.
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