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- Title
Intestinal proinflammatory macrophages induce a phenotypic switch in interstitial cells of Cajal.
- Authors
Xuyong Chen; Xinyao Meng; Hongyi Zhang; Chenzhao Feng; Bin Wang; Ning Li; Abdullahi, Khalid Mohamoud; Xiaojuan Wu; Jixin Yang; Zhi Li; Chunlei Jiao; Jia Wei; Xiaofeng Xiong; Kang Fu; Lei Yu; Besner, Gail E.; Jiexiong Feng; Chen, Xuyong; Meng, Xinyao; Zhang, Hongyi
- Abstract
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-α 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-α neutralization led to recovery of ICC phenotype and restored their pacemaker function. In isolated ICCs, TNF-α-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-α/NF-κB/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.
- Subjects
INTERSTITIAL cells; MACROPHAGE activation; PACEMAKER cells; MACROPHAGES; COLON (Anatomy); CELL metabolism; RNA metabolism; ANIMAL experimentation; CELL receptors; CELLS; CELLULAR signal transduction; COMPARATIVE studies; HIRSCHSPRUNG'S disease; IMMUNITY; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; RNA; TUMOR necrosis factors; DNA-binding proteins; EVALUATION research; ENTEROCOLITIS
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 12, p6443
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI126584