An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD. Academic Article uri icon

Overview

abstract

  • Efferocytosis of apoptotic neutrophils by macrophages following tissue injury is fundamental to the resolution of inflammation and initiation of tissue repair. Using a sterile peritonitis model in mice, we identified interleukin (IL)-4-producing efferocytosing macrophages in the peritoneum that activate invariant natural killer T (iNKT) cells to produce cytokines including IL-4, IL-13, and interferon-γ. Importantly, IL-4 from macrophages contributes to alternative activation of peritoneal exudate macrophages and augments type 2 cytokine production from NKT cells to suppress inflammation. The increased peritonitis in mice deficient in IL-4, NKT cells, or IL-4Rα expression on myeloid cells suggested that each is a key component for resolution of sterile inflammation. The reduced NAD phosphate oxidase is also critical for this model, because in mice with X-linked chronic granulomatous disease (X-CGD) that lack oxidase subunits, activation of iNKT cells by X-CGD peritoneal exudate macrophages was impaired during sterile peritonitis, resulting in enhanced and prolonged inflammation in these mice. Therefore, efferocytosis-induced IL-4 production and activation of IL-4-producing iNKT cells by macrophages are immunomodulatory events in an innate immune circuit required to resolve sterile inflammation and promote tissue repair.

authors

  • Zeng, Melody
  • Pham, Duy
  • Bagaitkar, Juhi
  • Liu, Jianyun
  • Otero, Karel
  • Shan, Ming
  • Wynn, Thomas A
  • Brombacher, Frank
  • Brutkiewicz, Randy R
  • Kaplan, Mark H
  • Dinauer, Mary C

publication date

  • February 20, 2013

Research

keywords

  • Genetic Diseases, X-Linked
  • Granulomatous Disease, Chronic
  • Inflammation
  • Interleukin-4
  • Macrophages
  • Natural Killer T-Cells
  • Phagocytosis

Identity

PubMed Central ID

  • PMC3637016

Scopus Document Identifier

  • 84879381908

Digital Object Identifier (DOI)

  • 10.1182/blood-2012-10-461913

PubMed ID

  • 23426944

Additional Document Info

volume

  • 121

issue

  • 17