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 Brutkiewicz, Mark Kaplan, Mary C. Dinauer

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

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

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Natural Killer T-Cells
T-cells
Macrophages
Interleukin-4
Inflammation
Networks (circuits)
Peritonitis
Chronic Granulomatous Disease
Chemical activation
Peritoneal Macrophages
Exudates and Transudates
Tissue
Oxidoreductases
Repair
Cytokines
Interleukin-13
Interleukins
Peritoneum
Myeloid Cells
NAD

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD. / Zeng, Melody Yue; Pham, Duy; Bagaitkar, Juhi; Liu, Jianyun; Otero, Karel; Shan, Ming; Wynn, Thomas A.; Brombacher, Frank; Brutkiewicz, Randy; Kaplan, Mark; Dinauer, Mary C.

In: Blood, Vol. 121, No. 17, 25.04.2013, p. 3473-3483.

Research output: Contribution to journalArticle

Zeng, MY, Pham, D, Bagaitkar, J, Liu, J, Otero, K, Shan, M, Wynn, TA, Brombacher, F, Brutkiewicz, R, Kaplan, M & Dinauer, MC 2013, 'An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD.', Blood, vol. 121, no. 17, pp. 3473-3483. https://doi.org/10.1182/blood-2012-10-461913
Zeng, Melody Yue ; Pham, Duy ; Bagaitkar, Juhi ; Liu, Jianyun ; Otero, Karel ; Shan, Ming ; Wynn, Thomas A. ; Brombacher, Frank ; Brutkiewicz, Randy ; Kaplan, Mark ; Dinauer, Mary C. / An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD. In: Blood. 2013 ; Vol. 121, No. 17. pp. 3473-3483.
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