Collagen-binding integrin α1β1 regulates intestinal inflammation in experimental colitis

Abstract

Central to inflammatory responses are the integrin-mediated adhesive interactions of cells with their ECM-rich environment. We investigated the role of the collagen-binding integrin α1β1 in intestinal inflammation using the mouse model of colitis induced by dextran sodium sulfate (DSS). mAb's directed against murine α1 were found to significantly attenuate inflammation and injury in DSS-treated wild-type mice; similar protection was seen in mice deficient for α1β1 integrin. Blockade or loss α1β1 was also associated with decreased mucosal inflammatory cell infiltrate and cytokine production. Importantly, we demonstrated that development and α1-mediated inhibition of DSS-induced colitis occurred independently of lymphocytes (Rag-2-/- mice), and identified the monocyte as a key α1β1-expressing cell type involved in the development of colitis in this model. In response to DSS, both α1 deficiency and anti-α1 mAb treatment significantly reduced monocyte accumulation and activation within the lamina propria. In summary, the data demonstrate that engagement of leukocyte-associated α1β1 receptors with ECM plays a pivotal role in mediating intestinal inflammation via promotion of monocyte movement and/or activation within the inflamed interstitium. Therapeutic strategies designed to disrupt such interactions may prove beneficial in treating intestinal inflammation.