Card9 Protects Sepsis by Regulating Ripk2-mediated Activation of NLRP3 Inflammasome in Macrophages

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 May 26

PMID 35618701

Authors

Zhen Xu

Daoqian Li

Wei Qu

Yuxin Yin

Shuping Qiao

Yanan Zhu

Sunan Shen

Yayi Hou

Jie Yang

Tingting Wang

Affiliations

Soon will be listed here.

Abstract

Sepsis is characterized by systemic inflammation, it's caused by primary infection of pathogenic microorganisms or secondary infection of damaged tissue. In this study, we focus on sepsis-induced intestine barrier functional disturbalice, presenting as increased permeability of intestinal epithelium. We observed that the phenotype of LPS-induced sepsis was exacerbated in Card9 mice, especially displaying more serious intestinal inflammation and gut barrier dysfunction. Next, we found the hyperactivation of NLRP3 inflammasome in the intestinal macrophages of Card9-sepsis mice. Moreover, Card9 over-expression decreased NLRP3 inflammasome activation in macrophages. Furthermore, we found that Card9 inhibited NLRP3 inflammasome activation by recruiting Ripk2. The competitive binding between Ripk2 with Caspase-1, instead of ASC with Caspase-1, inhibited the NLRP3 inflammasome activation. Over-expression of Ripk2 alleviated septic intestinal injury caused by Card9 deficiency. Taken together, we suggested Card9 acts as a negative regulation factor of NLRP3 inflammasome activation, which protects against intestinal damage during sepsis. Therefore, maintaining Card9-Ripk2 signaling homeostasis may provide a novel therapy of septic intestinal damage.

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