Mucosal inflammation induced by commensal bacteria-derived metabolites and host genetic disorder

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Flavell, Richard

Abstract

Mammalian mucosal tissues are the major interfaces for host-environment interaction. Naturally, these tissues face unique immunological challenges in terms of maintaining the normal functions of the organ and mount fine-tuned immune response against possible environmental cues including microbes, food antigens, air pollutants and ultraviolets. The inflammasome is an important defense mechanism that bridges the sensing of environmental microbial or danger signals to the initiation of proinflammatory responses. Indeed, human genome wide association studies (GWAS) and studies of rare diseases have suggested the biological significance of inflammasome in mucosal inflammatory diseases including inflammatory bowel diseases (IBD), pulmonary fibrosis, skin inflammatory syndrome and female genital tract inflammation. Commensal bacteria habitat the mucosal tissue and can interact with the host through the production small molecule metabolites. Despite the vast diversity of microbiota-derived metabolites, their impact on host physiology and disease remains poorly understood. To elucidate how commensal bacteria contribute to mucosal inflammatory response, we screened 437 bacterial strains isolated from diverse human mucosal sites including gut, vagina, skin, lung and oral cavity, for metabolites that induce proinflammatory cytokine IL-1β secretion in macrophages. Through forward chemical screening, genetic/pharmacological perturbations, sequencing-based unbiased mechanistic studies, we discovered a novel host innate sensing mechanism triggered by the microbial metabolite: butyrate. Our finding reveals that host cells exploit repetitive elements to accumulate cytoplasmic DNA-RNA hybrids as danger signals in response to the epigenetic modification induced by butyrate. This mechanism potentially underlies the bacterial induced female genital tract inflammation and adverse pregnancy outcome. Genetic mutations on varies inflammasome pathways have been reported to cause or be associated with mucosal inflammation. Dipeptidyl peptidase 9 (DPP9) and closely related dipeptidyl peptidase 8 (DPP8) are negative regulators for NLRP1 and human-specific CARD8 inflammasome pathways. Biallelic DPP9 loss of function variants lead to immune-associated defects affecting skin and lung barrier tissues. Genome-wide association studies (GWAS) have identified SNPs located within the intronic regions of DPP9 associated with severe SARS-CoV-2 infection and idiopathic pulmonary fibrosis (IPF). To unveil the pathogenesis of lung inflammation caused by loss of negative regulation on NLRP1 inflammasome, we ablated Dpp8 and Dpp9 (DKO) in mouse myeloid cells. The DKO mice exhibit a type I immune response in the lung characterized by an excess of activated T cells that aberrantly secrete IFNγ. We identified NLRP1 inflammasome regulated cytokine IL-18 as an essential driver of lung inflammation in DKO mice. With human monocytes, we found DPP9 restricts CARD8 activation and IL-18 secretion. Moreover, we identified human DPP9 as a novel susceptibility gene for checkpoint inhibitor pneumonitis (CIP) which is also characterized by type I immune response in the lung. In summary, this thesis presents two studies that characterize mucosal inflammation resulting from dysregulated inflammasomes or inflammasome-regulated cytokines. Both mucosal microbiota and host genetic disorders are identified as key drivers of mucosal inflammation.

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