PI(3)P-p40phox binding regulates NADPH oxidase activation in mouse macrophages and magnitude of inflammatory responses in vivo.

PI(3)P-p40phox binding regulates NADPH oxidase activation in mouse macrophages and magnitude of inflammatory responses in vivo.

J Leukoc Biol. 2016 Aug 19;

Authors: Bagaitkar J, Barbu EA, Perez-Zapata LJ, Austin A, Huang G, Pallat S, Dinauer MC

Abstract
Mutations in the leukocyte NADPH oxidase that abrogate superoxide production result in chronic granulomatous disease (CGD), an inherited immunodeficiency associated with recurrent infections and inflammatory complications. The cytosolic regulatory subunit p40(phox) plays a specialized role in stimulating NADPH oxidase activity on intracellular membranes via its phosphatidylinositol 3-phosphate [PI(3)P]-binding domain, as revealed by studies largely focused on neutrophils. Whether PI(3)P-p40(phox)-regulated superoxide production contributes to regulating inflammatory responses is not well understood. Here, we report that mice expressing p40(phox) R58A, which lacks PI(3)P binding, had impaired macrophage NADPH oxidase activity and increased sterile inflammation. p40(phoxR58A/R58A) macrophages exhibited diminished phagosome reactive oxygen species (ROS) in response to certain particulate and soluble ligands, including IgG-opsonized particles and a TLR2 agonist, along with unexpected defects in plasma membrane oxidase activity. Compared with wild-type (WT) mice, p40(phoxR58A/R58A) mice had elevated numbers of newly recruited neutrophils and monocytes in peritoneal inflammation elicited by zymosan, monosodium urate (MSU) crystals, or sodium periodate. At later time points, higher numbers of inflammatory macrophages in p40(phoxR58A/R58A) mice were consistent with delayed resolution. Our studies demonstrate a critical role of PI(3)P-p40(phox) binding for optimal activation of the NADPH oxidase in macrophages. Furthermore, selective loss of PI(3)P-regulated NADPH oxidase activity was sufficient to enhance significantly responses to inflammation and delay resolution.

PMID: 27543673 [PubMed - as supplied by publisher]

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