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SHIP negatively regulates type II immune responses in mast cells and macrophages
Author(s) -
Dobranowski Peter,
Sly Laura M.
Publication year - 2018
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.3mir0817-340r
Subject(s) - degranulation , biology , mast cell , inflammation , immune system , cytokine , immunology , receptor , microbiology and biotechnology , innate immune system , interleukin 33 , interleukin , biochemistry
SHIP is a hematopoietic‐specific lipid phosphatase that dephosphorylates PI3K‐generated PI(3,4,5)‐trisphosphate. SHIP removes this second messenger from the cell membrane blunting PI3K activity in immune cells. Thus, SHIP negatively regulates mast cell activation downstream of multiple receptors. SHIP has been referred to as the “gatekeeper” of mast cell degranulation as loss of SHIP dramatically increases degranulation or permits degranulation in response to normally inert stimuli. SHIP also negatively regulates Mϕ activation, including both pro‐inflammatory cytokine production downstream of pattern recognition receptors, and alternative Mϕ activation by the type II cytokines, IL‐4, and IL‐13. In the SHIP‐deficient (SHIP −/− ) mouse, increased mast cell and Mϕ activation leads to spontaneous inflammatory pathology at mucosal sites, which is characterized by high levels of type II inflammatory cytokines. SHIP −/− mast cells and Mϕs have both been implicated in driving inflammation in the SHIP −/− mouse lung. SHIP −/− Mϕs drive Crohn's disease‐like intestinal inflammation and fibrosis, which is dependent on heightened responses to innate immune stimuli generating IL‐1, and IL‐4 inducing abundant arginase I. Both lung and gut pathology translate to human disease as low SHIP levels and activity have been associated with allergy and with Crohn's disease in people. In this review, we summarize seminal literature and recent advances that provide insight into SHIP's role in mast cells and Mϕs, the contribution of these cell types to pathology in the SHIP −/− mouse, and describe how these findings translate to human disease and potential therapies.