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

Blood. 2013 Apr 25;121(17):3473-83. doi: 10.1182/blood-2012-10-461913. Epub 2013 Feb 20.

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.

Publication types

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

MeSH terms

  • Animals
  • Cytokines / metabolism
  • Genetic Diseases, X-Linked / immunology*
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Diseases, X-Linked / pathology
  • Granulomatous Disease, Chronic / immunology*
  • Granulomatous Disease, Chronic / metabolism
  • Granulomatous Disease, Chronic / pathology
  • Inflammation / immunology
  • Inflammation / pathology
  • Inflammation / prevention & control*
  • Interferon-gamma / metabolism
  • Interleukin-4 / physiology*
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Natural Killer T-Cells / pathology
  • Peritoneal Diseases / immunology
  • Peritoneal Diseases / pathology
  • Peritoneal Diseases / prevention & control
  • Phagocytosis / physiology*
  • Receptors, Cell Surface / physiology

Substances

  • Cytokines
  • Il4ra protein, mouse
  • Receptors, Cell Surface
  • Interleukin-4
  • Interferon-gamma