P142 CONSTITUTIVELY ACTIVE MAC-1 (CD11B) AMELIORATES INFLAMMATION IN MOUSE DSS COLITIS MODEL

Abstract

Mac-1 (CD11b/CD18)-is an integrin expressed on bone marrow-derived immune cells that binds ICAM-1 to regulate leukocyte adhesion and migration across the endothelium or epithelium. The role of CD11b in tumorigenesis and colitis is controversial. It has been reported that deficiency of CD11b exacerbates dextran sodium sulfate (DSS)-induced colitis. The opposite scenario, in which CD11b deficiency suppresses intestinal tumor growth in CD11b -/- APC min/+ animals by reducing myeloid cell recruitment has also been reported. Additional studies have concluded that an active CD11b signal can exert an inhibitory effect on TLR triggered inflammatory response in macrophages and even inhibit full T cells activation by myeloid dendritic cells. Clinical trials using agents designed to inhibit the binding of this integrin to its ligands have had limited success in humans. In this initial exploratory study, we compared the absence and the permanent activation of CD11b to further clarify the role of Mac-1 in the DSS colitis model. CD11bKO, CD11bKI-expressing constitutively active CD11b, and their corresponding littermates were treated with 4% DSS to induce colitis. Disease activity index and percentage weight loss were recorded. Distal colons were collected for the DSS as well as the water treated controls. Pathology scores were assigned following scoring criteria described in Erben et al., 2014 Flow cytometry immunophenotyping of lamina propria leukocytes was used to determine infiltrate composition and quantify myeloid-derived suppressor cells (MDSCs) defined by CD11b+/Gr-1+ expression. CD4 immunofluorescence was used for inter-strain comparison of effector T cell abundance. We also performed experiments to ascertain the effects of a CD11b agonist: Leukadherin-1 (LA1). Animals lacking CD11b expression were the least inflamed, while the constitutive activation of CD11b resulted in a decrease in the level of inflammation in relation to the C57 wild type group as per disease activity index and percentage weight loss. Ratios of neutrophil counts in DSS and untreated animals showed a higher neutrophilic infiltration in C57 animals while the CD11bKO displayed the lowest number.The number of CD4+ T cells and MDSCs present correlated with the levels of inflammation in these three strains. Use of LA1 resulted in intermediate levels of inflammation comparable to that observed in CD11bKI. Although more work needs to be done to elucidate the role of CD11b in colitis, our initial findings suggest that whether by dampening leukocyte migration and/or inhibiting full T cells activation during antigen presentation, constitutive activation of CD11b ameliorates inflammation in DSS treated animals. Therefore making CD11b is a worthy pharmacological target in the treatment of inflammatory diseases.