SHIP deficient macrophages promote inflammation by supporting the generation of Th17 cells (91.5)

Abstract

Abstract SHIP is an SH2-containing inositol phosphatase expressed in all hematopoietic cells and proposed as negative regulator of the immune response. SHIP-null mice show increased mortality due to a myeloproliferative-like syndrome. To better understand the function of SHIP we used a conditional disruption of SHIP in the macrophage-monocyte lineage (LysMcreSHIPfl/fl), which partially recapitulates the myeloproliferative phenotype of the null deletion. Macrophages from LysMcre SHIPfl/fl mice display an M2 phenotype likely due to enhanced signaling through the GM-CSF receptor. Deletion of SHIP in macrophages not only leads to myeloid hyperproliferation, but also to lymphocyte activation as a secondary effect. LysMcreSHIPfl/fl conditional mice develop splenomegaly with a large number of activated lymphocytes. We determined that T cells in these mice are biased towards the Th17 phenotype and expand the regulatory population. LysMcreSHIPfl/fl mice show higher mortality and greater induction of Th17 cells in the autoimmune model of EAE. Taken together, we have uncovered a specific regulatory role of SHIP signaling in macrophages that has important consequences in negatively regulating macrophage function directly and T cell development indirectly.