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

Abstract

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.

SHIP-1 Regulates Phagocytosis and M2 Polarization Through the PI3K/Akt–STAT5–Trib1 Circuit in Pseudomonas aeruginosa Infection

“…The Src homology 2-containing inositol 5-phosphatase, SHIP-1, is a 145-kDa protein highly expressed in hematopoietic cells (1). SHIP-1 negatively regulates phosphatidylinositol 3-kinase (PI3K) activity through hydrolysis of the 5 ′ -phosphate from the PI3K lipid product phosphatidylinositol 3,4,5-triphosphate [PI (3,4,5) P3] to phosphatidylinositol (3,4)-bisphosphate (PI (3,4) P2) (2). The PI3K-Akt pathway affects a spectrum of cellular functions including metabolism, growth, proliferation, survival, and adhesion (3).…”

“…The PI3K-Akt pathway affects a spectrum of cellular functions including metabolism, growth, proliferation, survival, and adhesion (3). Mast cells and macrophages, which are essential for the negative regulation of type II immune responses to drive lung spontaneous inflammation and injury, are over-activated in SHIP-1 −/− mice after Candida albicans infection (4). Pulmonary inflammation and M2-polarized macrophages were greatly exacerbated in SHIP-1 −/− BALB/c mice (5).…”

Phosphatidylinositol 3-kinase p110δ drives intestinal fibrosis in SHIP deficiency

“…14 PI3K phosphorylates phosphatidylinositol 4,5bisphoshophate (PI(4,5)P 2 ) to generate PI(3,4,5)P 3 , a critical second messenger. 15 PI3K consists of a regulatory subunit (p85α, p85β, p55α, or p55γ) and a catalytic subunit (p110α, p110β, p110γ, or p110δ). 15 The isoforms of the catalytic subunit perform distinct functions within cells.…”

“…15 PI3K consists of a regulatory subunit (p85α, p85β, p55α, or p55γ) and a catalytic subunit (p110α, p110β, p110γ, or p110δ). 15 The isoforms of the catalytic subunit perform distinct functions within cells. 15 Guo et al 16 created mice with a point mutation (D→A) in the active site of PI3Kp110δ.…”

“…15 The isoforms of the catalytic subunit perform distinct functions within cells. 15 Guo et al 16 created mice with a point mutation (D→A) in the active site of PI3Kp110δ. These mice, designated PI3Kp110δ D910A/D910A , have no p110δ catalytic activity but retain normal protein levels of all p110 catalytic subunit isoforms.…”