Loss of primary cilia promotes inflammation and carcinogenesis

• Published in: EMBO reports Vol. 23; no. 12; pp. e55687 - n/a
• Main Authors: Paul, Conception, Tang, Ruizhi, Longobardi, Ciro, Lattanzio, Rossano, Eguether, Thibaut, Turali, Hulya, Bremond, Julie, Maurizy, Chloé, Gabola, Monica, Poupeau, Sophie, Turtoi, Andrei, Denicolai, Emilie, Cufaro, Maria Concetta, Svrcek, Magali, Seksik, Philippe, Castronovo, Vincent, Delvenne, Philippe, de Laurenzi, Vincenzo, Da Costa, Quentin, Bertucci, François, Lemmers, Bénédicte, Pieragostino, Damiana, Mamessier, Emilie, Janke, Carsten, Pinet, Valérie, Hahne, Michael
• Format: Journal Article Web Resource
• Language: English
• Published: London Nature Publishing Group UK 06.12.2022; Springer Nature B.V; EMBO Press; John Wiley and Sons Inc
• Subjects: Anatomie (cytologie, histologie, embryologie...) & physiologie; Anatomy (cytology, histology, embryology...) & physiology; Animal biology; Animals; Biochemistry; Biochemistry, Molecular Biology; Biopsy; Cancer; Carcinogenesis; Carcinogens; Cellular Biology; Cilia; colitis; Colon; colon carcinogenesis; colonic fibroblasts; Colorectal cancer; Colorectal carcinoma; Cytokines; Dextran; Dextrans; EMBO03; EMBO05; EMBO19; Fibroblasts; Genetics; Immunology; inflammation; Inflammatory bowel disease; Inflammatory bowel diseases; Interleukin 6; Interleukin-6 - genetics; Life Sciences; Mice; Molecular Biology; Mouse devices; primary cilia; Sciences du vivant; Secretome; Signaling; Sodium sulfate; Ulcerative colitis; colonic fibroblasts; colitis; colon carcinogenesis; inflammation; primary cilia; inflammation Subject Categories Cancer; Immunology; Cell Adhesion; Polarity & Cytoskeleton
• ISSN: 1469-221X; 1469-3178; 1469-3178
• DOI: 10.15252/embr.202255687

Primary cilia (PC) are important signaling hubs, and we here explored their role in colonic pathology. In the colon, PC are mostly present on fibroblasts, and exposure of mice to either chemically induced colitis‐associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)‐induced acute colitis decreases PC numbers. We generated conditional knockout mice with reduced numbers of PC on colonic fibroblasts. These mice show increased susceptibility to CAC, as well as DSS‐induced colitis. Secretome and immunohistochemical analyses of DSS‐treated mice display an elevated production of the proinflammatory cytokine IL‐6 in PC‐deficient colons. An inflammatory environment diminishes PC presence in primary fibroblast cultures, which is triggered by IL‐6 as identified by RNA‐seq analysis together with blocking experiments. These findings suggest an activation loop between IL‐6 production and PC loss. An analysis of PC presence on biopsies of patients with ulcerative colitis or colorectal cancer (CRC) reveals decreased numbers of PC on colonic fibroblasts in pathological compared with surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC. Synopsis Primary cilia are present on colonic fibroblasts and their decrease in number promotes colitis and colon carcinogenesis. In colitis, primary cilia loss appears to be ultimately linked to IL‐6 signaling. Primary cilia (PC) are present on colonic fibroblasts. Induction of either acute colitis or colitis‐associated colon carcinogenesis in mice decreases PC numbers. Primary cilia deficiency promotes colonic pathologies. PC numbers on colonic fibroblasts in biopsies of ulcerative colitis or colorectal cancer patients are decreased. Graphical Abstract Primary cilia are present on colonic fibroblasts and their decrease in number promotes colitis and colon carcinogenesis. In colitis, primary cilia loss appears to be ultimately linked to IL‐6 signaling.