IL-17 promotes neutrophil-mediated immunity by activating microvascular pericytes and not endothelium

R Liu, HM Lauridsen, RA Amezquita… - The Journal of …, 2016 - journals.aai.org
The Journal of Immunology, 2016journals.aai.org
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 …
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.
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