Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation.
Epithelial myosin light chain kinase (MLCK)-dependent barrier dysfunction contributes to the pathogenesis of inflammatory bowel diseases (IBD). We reported that epithelial GM-CSF-STAT5 signalling is essential for intestinal homeostatic response to gut injury. However, mechanism, redundancy by STAT5 or cell types involved remained foggy. We here generated intestinal epithelial cell (IEC)-specific STAT5 knockout mice, these mice exhibited a delayed mucosal wound healing and dysfunctional intestinal barrier characterized by elevated levels of NF-κB activation and MLCK, and a reduction of zonula occludens expression in IECs. Deletion of MLCK restored intestinal barrier function in STAT5 knockout mice, and facilitated mucosal wound healing. Consistently, knockdown of stat5 in IEC monolayers led to increased NF-κB DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which were potentiated by administration of tumour necrosis factor-α (TNF-α), and prevented by concurrent NF-κB knockdown. Collectively, enterocyte STAT5 signalling protects against TJ barrier dysfunction and promotes intestinal mucosal wound healing via an interaction with NF-κB to suppress MLCK. Targeting IEC STAT5 signalling may be a novel therapeutic approach for treating intestinal barrier dysfunction in IBD.
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center (CCHMC), Cincinnati, OH, USA.
Shila
S
Gilbert
Rongli
R
Zhang
Lee
L
Denson
Richard
R
Moriggl
Kris
K
Steinbrecher
Noah
N
Shroyer
James
J
Lin
Xiaonan
X
Han
D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing
D050799:STAT5 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D009219:Myosin-Light-Chain Kinase