Neutrophil extracellular traps aggravate intestinal epithelial necroptosis in ischaemia–reperfusion by regulating TLR4/RIPK3/FUNDC1‐required mitophagy

Author:

Chu Chengnan1ORCID,Wang Xinyu1ORCID,Chen Fang2ORCID,Yang Chao1,Shi Lin3,Xu Weiqi1,Wang Kai1,Liu Baochen1,Wang Chenyang4,Sun Dongping3,Li Jieshou1,Ding Weiwei12ORCID

Affiliation:

1. Division of Trauma and Acute Care Surgery, Department of Surgery, Jinling Hospital, Affiliated Hospital of Medical School Nanjing University Nanjing Jiangsu Province China

2. Division of Trauma and Acute Care Surgery, Jinling Hospital, School of Medicine Southeast University Nanjing Jiangsu Province China

3. Institute of Chemicobiology and Functional Materials, School of Chemistry and Chemical Engineering Nanjing University of Science and Technology Nanjing Jiangsu Province China

4. Key Laboratory of Intestinal Injury, Research Institute of General Surgery, Affiliated Jinling Hospital Medical School of Nanjing University Nanjing Jiangsu China

Abstract

AbstractNeutrophil extracellular trap (NET) has been confirmed to be related to gut barrier injury during intestinal ischaemia–reperfusion (II/R). However, the specific molecular regulatory mechanism of NETs in II/R‐induced intestinal barrier damage has yet to be fully elucidated. Here, we reported increased NETs infiltration accompanied by elevated inflammatory cytokines, cellular necroptosis and tight junction disruption in the intestine of human II/R patients. Meanwhile, NETs aggravated Caco‐2 intestinal epithelial cell necroptosis, impairing the monolayer barrier in vitro. Moreover, Pad4‐deficient mice were used further to validate the role of NETs in II/R‐induced intestinal injury. In contrast, NET inhibition via Pad4 deficiency alleviated intestinal inflammation, attenuated cellular necroptosis, improved intestinal permeability, and enhanced tight junction protein expression. Notably, NETs prevented FUN14 domain‐containing 1 (FUNDC1)‐required mitophagy activation in intestinal epithelial cells, and stimulating mitophagy attenuated NET‐associated mitochondrial dysfunction, cellular necroptosis, and intestinal damage. Mechanistically, silencing Toll‐like receptor 4 (TLR4) or receptor‐interacting protein kinase 3 (RIPK3) via shRNA relieved mitophagy limitation, restored mitochondrial function and reduced NET‐induced necroptosis in Caco‐2 cells, whereas this protective effect was reversed by TLR4 or RIPK3 overexpression. The regulation of TLR4/RIPK3/FUNDC1‐required mitophagy by NETs can potentially induce intestinal epithelium necroptosis.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Cell Biology,General Medicine

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