RIP2 promotes FcγR-mediated reactive oxygen species production

J Biol Chem. 2019 Jun 28;294(26):10365-10378. doi: 10.1074/jbc.RA118.007218. Epub 2019 May 21.

Abstract

Receptor-interacting protein 2 (RIP2) is a kinase that mediates signaling downstream of the bacterial peptidoglycan sensors NOD1 and NOD2. Genetic loss or pharmaceutical inhibition of RIP2 has been shown to be beneficial in multiple inflammatory disease models with the effects largely attributed to reducing proinflammatory signaling downstream of peptidoglycan recognition. However, given the widespread expression of this kinase and its reported interactions with numerous other proteins, it is possible that RIP2 may also function in roles outside of peptidoglycan sensing. In this work, we show that RIP2 undergoes tyrosine phosphorylation and activation in response to engagement of the Fc γ receptor (FcγR). Using bone marrow-derived macrophages from WT and RIP2-KO mice, we show that loss of RIP2 leads to deficient FcγR signaling and reactive oxygen species (ROS) production upon FcγR cross-linking without affecting cytokine secretion, phagocytosis, or nitrate/nitrite production. The FcγR-induced ROS response was still dependent on NOD2, as macrophages deficient in this receptor showed similar defects. Mechanistically, we found that different members of the Src family kinases (SFKs) can promote RIP2 tyrosine phosphorylation and activation. Altogether, our findings suggest that RIP2 is functionally important in pathways outside of bacterial peptidoglycan sensing and that involvement in such pathways may depend on the actions of SFKs. These findings will have important implications for future therapies designed to target this kinase.

Keywords: Fc receptor; Fc-γ receptor; Src; inflammation; reactive oxygen species (ROS); receptor interacting protein 2 (RIP2); signal transduction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Immunity, Innate / immunology
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phagocytosis
  • Phosphorylation
  • Reactive Oxygen Species / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinase 2 / physiology*
  • Receptors, IgG / genetics
  • Receptors, IgG / metabolism*
  • Signal Transduction

Substances

  • Cytokines
  • Fcgr1 protein, mouse
  • Reactive Oxygen Species
  • Receptors, IgG
  • Receptor-Interacting Protein Serine-Threonine Kinase 2
  • Ripk2 protein, mouse