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

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

Research output: Contribution to journalArticle

33 Scopus citations

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-g. Importantly, IL-4 from macrophages contributes to alternative activation of peritoneal exudate macrophages and augments type 2 cytokine production from NKTcells to suppress inflammation. The increased peritonitis in mice deficient in IL-4, NKTcells, or IL-4Ra 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.

Original languageEnglish (US)
Pages (from-to)3473-3483
Number of pages11
JournalBlood
Volume121
Issue number17
DOIs
StatePublished - Apr 25 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Zeng, M. Y., Pham, D., Bagaitkar, J., Liu, J., Otero, K., Shan, M., Wynn, T. A., Brombacher, F., Brutkiewicz, R. R., Kaplan, M. H., & Dinauer, M. C. (2013). An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD. Blood, 121(17), 3473-3483. https://doi.org/10.1182/blood-2012-10-461913