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

Juhi Bagaitkar, Emilia A. Barbu, Lizet J. Perez-Zapata, Anthony Austin, Guangming Huang, Sabine Pallat, Mary C. Dinauer

Research output: Contribution to journalArticle

12 Scopus citations

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 p40phox 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-p40phox-regulated superoxide production contributes to regulating inflammatory responses is not well understood. Here, we report that mice expressing p40phox R58A, which lacks PI(3)P binding, had impaired macrophage NADPH oxidase activity and increased sterile inflammation. p40phoxR58A/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, p40phoxR58A/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 p40phoxR58A/R58A mice were consistent with delayed resolution. Our studies demonstrate a critical role of PI(3) P-p40phox 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.

Original languageEnglish
Pages (from-to)449-457
Number of pages9
JournalJournal of Leukocyte Biology
Volume101
Issue number2
DOIs
StatePublished - Feb 2017

Keywords

  • CGD
  • ROS
  • Sterile inflammation

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