The crosstalk between colonic epithelium and fibroblasts plays a crucial role in colon homeostasis and pathology. An underexplored trait in this cellular dialogue are primary cilia (PC), an antennae‐like structure extruding from the surface of many mammalian cells. PC are cellular organelles serving as sensors of environmental signals. Abnormal ciliary function result in so-called ciliopathies, i.e. inherited disorders, such as cystic kidney diseases, but a causative role for PC in colonic pathology has been not yet suggested.
We found that PC in the colon are mostly expressed by colonic fibroblasts. To test whether altered PC number in the colon can increase the susceptibility to induced carcinogenesis we used the reference models for the analysis of PC, i.e. conditional knock-out mice for Kif3a and Ift88, two proteins essential in the maintenance of PC. Both mouse strains were crossed with collagenVI:cre mice to direct gene deletion in colonic fibroblasts. As the colVI promoter is only active in a subset of colonic fibroblast, we observed a decreased number, rather than total disappearance of PC. This was, however, sufficient to enhance chemically-induced colitis as well as carcinogenesis in the mutant mouse strains. In addition, secretome and immunohistochemical analyses of DSS-treated mice displayed an elevated production of the pro-inflammatory cytokine IL-6 in PC-deficient colons. An inflammatory environment diminished PC presence in primary fibroblast cultures, which was triggered by IL-6 as identified by RNAseq analysis together with blocking experiments. These findings suggest an activation loop between IL-6 production and PC loss during acute colitis. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide, for the first time, evidence that a decrease in colonic PC numbers in fibroblasts promotes colitis and CRC, therefore opening novel biomedical opportunities.
Paul C*, Tang R*, Longobardi C, Lattanzio R, Eguether T, Turali H, Bremond J, Maurizy C, Poupeau S, Turtoi A, Denicolai, E., Cufaro, M., Svrcek, M., Seksik, P., Castranovo, V., Delvenne, P., De Laurenzi, V., Da Costa, Q., Bertucci, F., Lemmers, B., Pieragostino, D., Mamessier, E., Janke, C., Pinet**, V., Hahne, M**. (2022) Loss of colonic primary cilia promotes inflammation and carcinogenesis.
EMBO Rep. 2022 Oct 25:e55687. doi: 10.15252/embr.202255687. (*) Co-first authors. (**) Co-last authors.