Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation.

Science Advances
Chunmei MaShuo Yang

Abstract

The functional relevance and mechanistic basis of the effects of the pyroptosis executioner Gasdermin D (GSDMD) on colitis remain unclear. In this study, we observed that GSDMD protein was activated during intestinal inflammation in a model of chemically induced colitis. GSDMD deficiency exacerbated experimental colitis independent of changes in the microbiota and without affecting the production of antimicrobial peptides. GSDMD deficiency in macrophages, but not epithelial cells, was sufficient to drive this exacerbated experimental colitis. We further demonstrate that GSDMD functions in macrophages as a negative regulator to control cyclic GMP-AMP synthase (cGAS)-dependent inflammation, thereby protecting against colitis. Moreover, the administration of cGAS inhibitor can rescue the colitogenic phenotype in GSDMD-deficient mice. Collectively, these findings provide the first demonstration of GSDMD's role in controlling colitis and a detailed delineation of the underlying mechanism.

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Citations

Jul 28, 2020·Immunological Reviews·Puja KumariVijay A Rathinam
Jan 25, 2021·Journal of Experimental & Clinical Cancer Research : CR·Qiongyuan HuWenxian Guan
Nov 5, 2020·International Journal of Molecular Sciences·Kohei Wagatsuma, Hiroshi Nakase

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Datasets Mentioned

BETA
PRJNA574780

Methods Mentioned

BETA
IEC
IECs
enzyme-linked immunosorbent assay
fluorescence-activated cell sorting
ELISA
FACS
RNA-seq
electrophoresis
flow cytometry
transfection

Software Mentioned

Trimmomatic
HISAT2
GSEA
UPARSE
FLASH
Tom
GraphPad Prism
FlowJo
Gene Set Enrichment Analysis ( GSEA )
Gene Network Analysis

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