A2.21 The role of HCK, FGR and LYN inin vivoinflammation in mice

Abstract

Background and objectives Although Src family kinases participate in leukocyte function in vitro , such as integrin signal transduction, their role in inflammation in vivo is poorly understood. The role of Src family kinases in b2 integrin signalling and the requirement for b2 integrins during autoantibody-induced in vivo inflammation prompted us to test the role of Src family kinases in autoantibody-induced inflammatory disease models. Materials and methods To determine the role of Src family kinases in autoantibody-induced autoimmune diseases Hck-/-Fgr-/-Lyn-/- triple knockout and wild type mice were tested in autoantibody-induced K/B×N serum transfer arthritis, autoantibody-induced skin blistering disease and reverse passive Arthus reaction. Autoimmune disease development was carefully monitored, and inflammatory cytokine and chemokine production was determined in vivo and in vitro . Furthermore, in vivo migratory capacity of leukocytes was monitored in mixed radiation chimaeras. Results We found that Src family kinases play a critical role in myeloid cell–mediated in vivo inflammatory reactions. Mice lacking the Src family kinases Hck, Fgr, and Lyn in the hematopoietic compartment were completely protected from autoantibody-induced arthritis and skin blistering disease, as well as from the reverse passive Arthus reaction, with functional overlap between the three kinases. Though the overall phenotype resembled the leukocyte recruitment defect observed in b2 integrin–deficient (CD18-/-) mice, Hck-/-Fgr-/-Lyn-/- neutrophils and monocytes/macrophages had no cell autonomous in vivo or in vitro migration defect. Instead, Src family kinases were required for the generation of the inflammatory environment in vivo and for the release of proinflammatory mediators from neutrophils and macrophages in vitro , likely due to their role in Fcg receptor signal transduction. Conclusions Our results suggest that infiltrating myeloid cells release proinflammatory chemokine, cytokine, and lipid mediators that attract further neutrophils and monocytes from the circulation in a CD18-dependent manner. Src family kinases are required for the generation of the inflammatory environment but not for the intrinsic migratory ability of myeloid cells.