| First Author | Chen X | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 12 | Pages | 6443-6456 |
| PubMed ID | 32809970 | Mgi Jnum | J:300277 |
| Mgi Id | MGI:6491833 | Doi | 10.1172/JCI126584 |
| Citation | Chen X, et al. (2020) Intestinal proinflammatory macrophages induce a phenotypic switch in interstitial cells of Cajal. J Clin Invest 130(12):6443-6456 |
| abstractText | Interstitial cells of Cajal (ICCs) are pacemaker cells in the intestine, and their function can be compromised by loss of C-KIT expression. Macrophage activation has been identified in intestine affected by Hirschsprung disease-associated enterocolitis (HAEC). In this study, we examined proinflammatory macrophage activation and explored the mechanisms by which it downregulates C-KIT expression in ICCs in colon affected by HAEC. We found that macrophage activation and TNF-alpha production were dramatically increased in the proximal dilated colon of HAEC patients and 3-week-old Ednrb-/- mice. Moreover, ICCs lost their C-KIT+ phenotype in the dilated colon, resulting in damaged pacemaker function and intestinal dysmotility. However, macrophage depletion or TNF-alpha neutralization led to recovery of ICC phenotype and restored their pacemaker function. In isolated ICCs, TNF-alpha-mediated phosphorylation of p65 induced overexpression of microRNA-221 (miR-221), resulting in suppression of C-KIT expression and pacemaker currents. We also identified a TNF-alpha/NF-kappaB/miR-221 pathway that downregulated C-KIT expression in ICCs in the colon affected by HAEC. These findings suggest the important roles of proinflammatory macrophage activation in a phenotypic switch of ICCs, representing a promising therapeutic target for HAEC. |
