title: IL-17 Promotes Neutrophil-Mediated Immunity by Activating Microvascular Pericytes and Not Endothelium.
abstract: A classical hallmark of acute inflammation is neutrophil infiltration of tissues, a multistep process that involves sequential cell-cell interactions of circulating leukocytes with IL-1- or TNF-activated microvascular endothelial cells (ECs) and pericytes (PCs) that form the wall of the postcapillary venules. The initial infiltrating cells accumulate perivascularly in close proximity to PCs. IL-17, a proinflammatory cytokine that acts on target cells via a heterodimeric receptor formed by IL-17RA and IL-17RC subunits, also promotes neutrophilic inflammation but its effects on vascular cells are less clear. We report that both cultured human ECs and PCs strongly express IL-17RC and, although neither cell type expresses much IL-17RA, PCs express significantly more than ECs. IL-17, alone or synergistically with TNF, significantly alters inflammatory gene expression in cultured human PCs but not ECs. RNA sequencing analysis identifies many IL-17-induced transcripts in PCs encoding proteins known to stimulate neutrophil-mediated immunity. Conditioned media from IL-17-activated PCs, but not ECs, induce pertussis toxin-sensitive neutrophil polarization, likely mediated by PC-secreted chemokines, and they also stimulate neutrophil production of proinflammatory molecules, including TNF, IL-1α, IL-1β, and IL-8. Furthermore, IL-17-activated PCs, but not ECs, can prolong neutrophil survival by producing G-CSF and GM-CSF, delaying the mitochondrial outer membrane permeabilization and caspase-9 activation. Importantly, neutrophils exhibit enhanced phagocytic capacity after activation by conditioned media from IL-17-treated PCs. We conclude that PCs, not ECs, are the major target of IL-17 within the microvessel wall and that IL-17-activated PCs can modulate neutrophil functions within the perivascular tissue space.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Rebecca
authors.identifier: 0000-0002-3761-7018
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520;
authors.forename: Holly M
authors.identifier: 0000-0002-0880-1086
authors.initials: HM
authors.lastname: Lauridsen
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; Howard Hughes Medical Institute, Chevy Chase, MD 20815;
authors.forename: Robert A
authors.identifier: 0000-0001-6868-7193
authors.initials: RA
authors.lastname: Amezquita
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520; and.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Pierce
authors.affiliation: Division of Cardiology, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516.
authors.forename: Dan
authors.initials: D
authors.lastname: Jane-Wit
authors.affiliation: Division of Cardiology, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516.
authors.forename: Caodi
authors.initials: C
authors.lastname: Fang
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520;
authors.forename: Amanda S
authors.initials: AS
authors.lastname: Pellowe
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Kirkiles-Smith
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06520;
authors.forename: Anjelica L
authors.initials: AL
authors.lastname: Gonzalez
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; jordan.pober@yale.edu.
authors.forename: Jordan S
authors.identifier: 0000-0001-5990-1071
authors.initials: JS
authors.lastname: Pober
mesh_terms: D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D003470:Culture Media; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D016179:Granulocyte Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology* / Q000502:physiology; D020286:Pericytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D053722:Receptors, Interleukin-17 / Q000276:immunology* / Q000502:physiology; D017423:Sequence Analysis, RNA; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology; D014699:Venules / Q000166:cytology / Q000276:immunology
chemical_list: D003470:Culture Media; D016207:Cytokines; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053453:Caspase 9