title: IL-17 stimulates differentiation of human anti-inflammatory macrophages and phagocytosis of apoptotic neutrophils in response to IL-10 and glucocorticoids.
abstract: Exposure of human monocytes/macrophages to anti-inflammatory agents, such as IL-10 or glucocorticoids, can lead to two separate fates: either Fas/CD95-mediated apoptosis or differentiation into regulatory and efferocytic M2c (CD14(bright)CD16(+)CD163(+)Mer tyrosine kinase(+)) macrophages. We found that the prevalent effect depends on the type of Th cytokine environment and on the stage of monocyte-to-macrophage differentiation. In particular, the presence of IFN-γ (Th1 inflammation) or the prolonged exposure to IL-4 (chronic Th2 inflammation) promotes apoptosis of monocytes/macrophages and causes resistance to M2c differentiation, thus provoking impaired clearance of apoptotic neutrophils, uncontrolled accumulation of apoptotic cells, and persistent inflammation. In contrast, the presence of IL-17 (Th17 environment) prevents monocyte/macrophage apoptosis and elicits intense M2c differentiation, thus ensuring efficient clearance of apoptotic neutrophils and restoration of anti-inflammatory conditions. Additionally, the Th environment affects the expression of two distinct Mer tyrosine kinase isoforms: IL-4 downregulates the membrane isoform but induces an intracellular and Gas6-dependent isoform, whereas IFN-γ downregulates both and IL-17 upregulates both. Our data support an unexpected role for IL-17 in orchestrating resolution of innate inflammation, whereas IFN-γ and IL-4 emerge as major determinants of IL-10 and glucocorticoid resistance.
authors.affiliation: Section of Rheumatology, Department of Medicine, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zizzo
authors.forename: Philip L
authors.initials: PL
authors.lastname: Cohen
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D002454:Cell Differentiation; D002478:Cells, Cultured; D005938:Glucocorticoids / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism / Q000494:pharmacology; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology; D008264:Macrophages / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis; D020033:Protein Isoforms; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D020381:Interleukin-17; D020033:Protein Isoforms; D019014:fas Receptor; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma