NLRP3 protects mice from radiation-induced colon and skin damage via attenuating cGAS-STING signaling

Tiancong Wu; Jianhua Gao; Wen Liu; Jian Cui; Miaofang Yang; Wenjie Guo; Fang-Yu Wang

doi:10.1016/j.taap.2021.115495

NLRP3 protects mice from radiation-induced colon and skin damage via attenuating cGAS-STING signaling

Toxicol Appl Pharmacol. 2021 May 1:418:115495. doi: 10.1016/j.taap.2021.115495. Epub 2021 Mar 17.

Authors

Tiancong Wu¹, Jianhua Gao², Wen Liu², Jian Cui², Miaofang Yang³, Wenjie Guo⁴, Fang-Yu Wang⁵

Affiliations

¹ Department of Gastroenterology and Hepatology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing 210002, China; Jinling Hospital, Department of Radiation Oncology, Nanjing University, School Medicine, Nanjing 210002, China.
² State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China.
³ Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing 210002, Jiangsu Province, China.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China. Electronic address: [email protected].
⁵ Department of Gastroenterology and Hepatology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing 210002, China; Department of Gastroenterology and Hepatology, Jinling Hospital, Medical School of Nanjing University, 305 Zhongshan East Road, Nanjing 210002, Jiangsu Province, China. Electronic address: [email protected].

PMID: 33741346
DOI: 10.1016/j.taap.2021.115495

Abstract

In the present study, the effects of NLRP3 on radiation-induced tissue damage, including colon and skin damage in mice, and the possible mechanisms were explored in vivo and in vitro. The mice were subjected to whole abdomen radiation by timed exposure to X-ray at a cumulative dose of 14 Gy. The survival rate showed that NLRP3 deficiency increased the mortality rate in mice. Furthermore, colon damage, evaluated by H&E staining and barrier function analysis, were significantly aggravated by NLRP3 deficiency. Enhanced phosphorylation of p-TBK1 and p-IRF3 in colonic tissue as well as elevated IFN-β levels in the serum indicated hyperactivation of cGAS-STING signaling. Moreover, radiation-induced expression of p-TBK1, p-IRF3, and IFN-β in BMDMs increased in vitro after NLRP3 knockout. Thus, our study outcomes suggest that NLRP3 may protect mice from radiation-induced tissue damage via attenuating cGAS-STING signaling.

Keywords: NLRP3 Inflammasome; Radiation; Tissue Damage; cGAS-STING.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cells, Cultured
Colon / enzymology
Colon / pathology
Colon / radiation effects*
Interferon Regulatory Factor-3 / metabolism
Interferon-beta / metabolism
Macrophages / enzymology
Macrophages / pathology
Macrophages / radiation effects*
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
Nucleotidyltransferases / metabolism*
Phosphorylation
Protein Serine-Threonine Kinases / metabolism
Radiation Injuries / enzymology
Radiation Injuries / genetics
Radiation Injuries / pathology
Radiation Injuries / prevention & control*
Signal Transduction
Skin / enzymology
Skin / pathology
Skin / radiation effects*
Skin Ulcer / enzymology
Skin Ulcer / genetics
Skin Ulcer / pathology
Skin Ulcer / prevention & control*

Substances

Interferon Regulatory Factor-3
Irf3 protein, mouse
Membrane Proteins
NLR Family, Pyrin Domain-Containing 3 Protein
Nlrp3 protein, mouse
Sting1 protein, mouse
Interferon-beta
Tbk1 protein, mouse
Protein Serine-Threonine Kinases
Nucleotidyltransferases
cGAS protein, mouse