IF1 inactivation attenuates experimental colitis through downregulation of neutrophil infiltration in colon mucosa.

Genshen Zhong, Jiaojiao Zhang, Ying Guo, Yichun Wang, Minna Wu, Jie Ren, Yuan Li, Xiaoying Zhang, Beiyan Zhou, Weidong Zhao, Yunwei Lou, Hui Wang, Jianping Ye

International immunopharmacology 2021 Oct

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IF1 is a mitochondrial protein involved in the regulation of ATP synthase activity. The role of IF1 remains to be established in inflammatory bowel diseases (IBD). In this study, we report that IF1 gene inactivation generated protection against IBD in the dextran sodium sulfate (DSS) model. IF1 gene knockout (IF1-KO) mice developed less severe colitis than the wild type (WT) mice as judged by parameters including disease activity index (DAI), body weight loss, inflammatory cytokines, leukocyte infiltration and bacterial invasion in the colon tissue. The intestinal barrier integrity was protected in the colon tissue of IF1-KO mice through a reduction in apoptosis and inflammasomal activity. The protection was abolished in the KO mice after substitution of the immune cells with the wild type cells following bone marrow transplantation. Depletion of neutrophils with anti-Gr-1 antibody abolished the protection from colitis in IF1-KO mice. Neutrophil number was decreased in the peripheral blood of IF1-KO mice, which was associated with a reduction in LC3A/B proteins in the KO neutrophils in Rapamycin-induced autophagy response. Inhibition of autophagy with the lysosome inhibitor Chloroquine (CQ) decreased the absolute number of neutrophils in WT mice and protected the mice from colitis. Taken together, these findings suggest that IF1 may contribute to the pathogenesis of IBD through acceleration of neutrophil autophagy. The activity is attenuated in the IF1-KO mice through reduction of autophagy in neutrophils leading to resistance to IBD. Copyright © 2021. Published by Elsevier B.V.

Citation

Genshen Zhong, Jiaojiao Zhang, Ying Guo, Yichun Wang, Minna Wu, Jie Ren, Yuan Li, Xiaoying Zhang, Beiyan Zhou, Weidong Zhao, Yunwei Lou, Hui Wang, Jianping Ye. IF1 inactivation attenuates experimental colitis through downregulation of neutrophil infiltration in colon mucosa. International immunopharmacology. 2021 Oct;99:107980