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Vitamin D 3 and carbamazepine protect against Clostridioides difficile infection in mice by restoring macrophage lysosome acidification
Hung Chan 1 2 3, Qing Li 1 2 3 4, Xiansong Wang 1 2, Wing Yingzhi Liu 1 2, Wei Hu 1 2 3, Judeng Zeng 1 2 3, Chuan Xie 1 2 3, Thomas Ngai Yeung Kwong 3 4 5, Idy Hiu Ting Ho 1 2 3, Xiaodong Liu 1 2 3, Huarong Chen 1 2 3 4, Jun Yu 3 4 5 6, Ho Ko 2 3 5, Raphael Chiu Yeung Chan 7, Margaret Ip 6 7, Tony Gin 1 2 3, Alfred Sze Lok Cheng 4 8, Lin Zhang 1 2 3 4 5, Matthew Tak Vai Chan 1 2 3, Sunny Hei Wong 3 4 5 6 9, William Ka Kei Wu 1 2 3 4 6
Abstract:
Clostridioides difficile infection (CDI) is a common cause of nosocomial diarrhea. TcdB is a major C. difficile exotoxin that activates macrophages to promote inflammation and epithelial damage. Lysosome impairment is a known trigger for inflammation. Herein, we hypothesize that TcdB could impair macrophage lysosomal function to mediate inflammation during CDI. Effects of TcdB on lysosomal function and the downstream pro-inflammatory SQSTM1/p62-NFKB (nuclear factor kappa B) signaling were assessed in cultured macrophages and in a murine CDI model. Protective effects of two lysosome activators (i.e., vitamin D3 and carbamazepine) were assessed. Results showed that TcdB inhibited CTNNB1/β-catenin activity to downregulate MITF (melanocyte inducing transcription factor) and its direct target genes encoding components of lysosomal membrane vacuolar-type ATPase, thereby suppressing lysosome acidification in macrophages. The resulting lysosomal dysfunction then impaired autophagic flux and activated SQSTM1-NFKB signaling to drive the expression of IL1B/IL-1β (interleukin 1 beta), IL8 and CXCL2 (chemokine (C-X-C motif) ligand 2). Restoring MITF function by enforced MITF expression or restoring lysosome acidification with 1α,25-dihydroxyvitamin D3 or carbamazepine suppressed pro-inflammatory cytokine expression in vitro. In mice, gavage with TcdB-hyperproducing C. difficile or injection of TcdB into ligated colon segments caused prominent MITF downregulation in macrophages. Vitamin D3 and carbamazepine lessened TcdB-induced lysosomal dysfunction, inflammation and histological damage. In conclusion, TcdB inhibits the CTNNB1-MITF axis to suppress lysosome acidification and activates the downstream SQSTM1-NFKB signaling in macrophages during CDI. Vitamin D3 and carbamazepine protect against CDI by restoring MITF expression and lysosomal function in mice.
PMID: 34989311
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