title: An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD.
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: Department of Pediatrics, Herman B Wells Center for Pediatric Research, Riley Hospital for Children, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, USA.
authors: Melody Yue
authors: MY
authors: Zeng
authors: Duy
authors: D
authors: Pham
authors: Juhi
authors: J
authors: Bagaitkar
authors: Jianyun
authors: J
authors: Liu
authors: Karel
authors: K
authors: Otero
authors: Ming
authors: M
authors: Shan
authors: Thomas A
authors: TA
authors: Wynn
authors: Frank
authors: F
authors: Brombacher
authors: Randy R
authors: RR
authors: Brutkiewicz
authors: Mark H
authors: MH
authors: Kaplan
authors: Mary C
authors: MC
authors: Dinauer
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D040181:Genetic Diseases, X-Linked / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006105:Granulomatous Disease, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000502:physiology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010532:Peritoneal Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D010587:Phagocytosis / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D016207:Cytokines; D007371:Interferon-gamma; D015847:Interleukin-4; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit