Vitamin D-3 and carbamazepine protect against Clostridioides difficile infection in mice by restoring macrophage lysosome acidification
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香港中文大學研究人員
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摘要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 D-3 and carbamazepine) were assessed. Results showed that TcdB inhibited CTNNB1/beta-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-1 beta (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 1 alpha,25-dihydroxyvitamin D-3 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 D-3 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 D-3 and carbamazepine protect against CDI by restoring MITF expression and lysosomal function in mice.
著者Chan H, Li Q, Wang XS, Liu WY, Hu W, Zeng JD, Xie C, Kwong TNY, Ho IHT, Liu XD, Chen HR, Yu J, Ko H, Chan RCY, Ip M, Gin T, Cheng ASL, Zhang L, Chan MTV, Wong SH, Wu WKK
期刊名稱Autophagy
出版年份2022
月份1
卷號18
期次9
出版社TAYLOR & FRANCIS INC
頁次2050 - 2067
國際標準期刊號1554-8627
語言英式英語
關鍵詞Autophagic flux, Clostridium difficile, macrophages, MITF, toxin B
Web of Science 學科類別Cell Biology;Cell Biology
