SHIP deficiency causes Crohn's disease-like ileitis

Kerr, William G; Park, Mi-Young; Maubert, Monique; Engelman, Robert W

The Src homology 2 (SH2)-containing inositol-5-phosphatase (SHIP) protein becomes tyrosine phosphorylated in haematopoietic cells following activation of surface receptors for various cytokines including erythropoietin, IL-3, GM-CSF, M-CSF, or in response to B cell antigen receptor cross-linking, or T cell activation. 29 30 SHIP signalling plays a pivotal role in limiting the number and function of immunoregulatory cells in the peripheral lymphoid system. 31e37 We recently found that SHIP limits the number of immunoregulatory T cells present in the spleen and mesenteric lymph nodes. 35 SHIP performs this role by controlling the number of Treg cells in the periphery either by limiting the survival of FoxP3 + Treg cells or by preventing the inappropriate acquisition of FoxP3 expression by naïve CD4 T cells. 35 Consistent with this finding, the p110 subunit of an enzyme that SHIP opposes, PI3K, is critical for the formation and survival of Treg cells in the periphery. 38 39 SHIP-deficiency also promotes the inappropriate expansion of myeloid immunoregulatory (MIR) cells in spleen and lymph nodes. 32 33 Thus, in major peripheral lymphoid tissues like spleen and lymph node, SHIP-deficiency leads to profound and functional expansion of immunoregulatory capacity. In aggregate these studies establish that inositol phospholipid signalling plays a pivotal role in the formation, homeostasis and function of both myeloid and lymphoid immunoregulatory cell populations. SHIP, through its 5 9 -inositol phosphatase domain, hydrolyses the second messenger PI(3,4,5)P 3 and thus limits PI3K activation of key downstream immune effector pathways such as Akt and NF-kB. 30 40 SHIP-deficient mice are smaller than their WT and heterozygous littermates and exhibit a greatly reduced lifespan with survival beyond 10e12 weeks of life observed only rarely, 32 41 attributable in part to the development of an eosinophilic crystalline pneumonia with infiltration by mixed inflammatory cells resulting in patchy lung consolidation. 41 Eosinophilic crystalline pneumonia is a cause of shortened life span in various genetically engineered mouse models. 42 43 Granulocytes are less susceptible to apoptotic signals in SHIP-deficient mice, and granulocyteemonocyte infiltrations can be found in the liver, kidney, heart, skeletal muscle, pancreas lymph nodes and thymus. 44 The increased capacity of SHIP-deficient T cells to differentiate into Treg cells is accompanied by a deficiency in Th17 cell differentiation and a reduced ability to cause colitis after adoptive transfer of CD4 + T cells to T cell deficient hosts. 35 36 Although SHIP expression and function has generally been thought to be confined to cells in the haematopoietic system, recent evidence indicates that SHIP is also expressed by some parenchymal cell types, including osteoblasts 45 and endothelial cells. 46 In fact, we recently identified the first known function for SHIP outside the haematolymphoid compartment as SHIP is required for support of haematopoietic stem cell function and quiescence by bone marrow (BM) niche cells. 45 Given its role in immune regulation and lymphoid function we sought to examine whether SHIP-deficiency might have consequences at enteric mucosal surfaces where greater stress is placed on both immune effector and regulatory processes due to the close and constant interaction with commensal microflora and potential pathogens at this organ site. Surprisingly, our analysis reveals a paucity o