Role of non-hematopoietic β-arrestin1 in intestinal inflammation (MUC2P.828)

• Published in: The Journal of immunology (1950) 2014-05, Vol.192 (1_Supplement), p.68-68.12
• Main Authors: Lee, Taehyung, Lee, Eunhee, Obey, Kimberly, Michelin, Erika, Chung, Misoo, Vlachos, Elena, Parameswaran, Narayanan
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.192.Supp.68.12

β-arrestin1 (β-arr1), an intracellular scaffolding protein has been shown to regulate inflammation by modulating Toll-like receptor (TLR) signaling in immune cells. We recently demonstrated that β-arr1 deficiency attenuates experimental colitis in mice. However the cell-type-specific role of β-arr1 in colitis is not known. To test this we generated bone marrow chimeras with β-arr1 deficiency only in non-hematopoietic compartment (non-hβ-arr1KO), and subjected the WT and non-hβ-arr1KO mice to DSS-induced colitis. Interestingly, our results demonstrate that β-arr1 expression in the non-hematopoietic compartment protects mice from early weight loss during colitis. To understand the signaling mechanisms, we knocked down β-arr1 in human intestinal epithelial cells (SW480) and tested the effect of TNF-α on MAPK and NFκB signaling pathways. Even though β-arr1 knockdown did not affect TNF-α-induced NFκB activation, p38 and JNK pathways were enhanced in the knockdown cells. Intriguingly, ERK1/2 activation by TNF-α was significantly inhibited in β-arr1-knockdown cells. Differential modulation of the MAPK signaling by β-arr1 could lead to higher apoptosis of intestinal epithelial cells in non-hβ-arr1 deficient mice. Together, our results demonstrate that β-arr1-dependent signaling in non-hematopoietic cells likely plays a critical role in the pathogenesis of colitis.