SHIP negatively regulates type II immune responses in mast cells and macrophages

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Peter Dobranowski¹  Laura M. Sly¹ 

[1] Division of Gastroenterology, Department of Pediatrics, BC Children's Hospital Research Institute;Department of Pediatrics, University of British Columbia

关键词: allergy;    Crohn’s disease;    degranulation;    lipid phosphatase;    macrophage alternative activation;    PI3K;   

DOI  :  10.1002/JLB.3MIR0817-340R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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 M? activation, including both pro-inflammatory cytokine production downstream of pattern recognition receptors, and alternative M? activation by the type II cytokines, IL-4, and IL-13. In the SHIP-deficient (SHIP−/−) mouse, increased mast cell and M? activation leads to spontaneous inflammatory pathology at mucosal sites, which is characterized by high levels of type II inflammatory cytokines. SHIP−/− mast cells and M?s have both been implicated in driving inflammation in the SHIP−/− mouse lung. SHIP−/− M?s 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 M?s, the contribution of these cell types to pathology in the SHIP−/− mouse, and describe how these findings translate to human disease and potential therapies.

【 授权许可】

CC BY