Innate cellular sources of interleukin-17A regulate macrophage accumulation in cigarette- smoke-induced lung inflammation in mice

TY - JOUR

T1 - Innate cellular sources of interleukin-17A regulate macrophage accumulation in cigarette- smoke-induced lung inflammation in mice

AU - Bozinovski, Steven

AU - Seow, Huei Jiunn

AU - Chan, Sheau Pyng Jamie

AU - Anthony, Desiree A

AU - McQualter, Jonathan Luke

AU - Hansen, Michelle J

AU - Jenkins, Brendan John

AU - Anderson, Gary

AU - Vlahos, Ross

PY - 2015

Y1 - 2015

N2 - Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD). Interleukin-17A (IL-17A) is a pivotal cytokine that regulates lung immunity and inflammation. The aim of this study was to investigate how IL-17A regulates CS-induced lung inflammation in vivo . IL-17A KO mice and neutralisation of IL-17A in WT mice reduced macrophage and neutrophil recruitment and CCL2, CCL3 and MMP-12 mRNA expression in response to acute CS exposure. IL-17A expression was increased in NOD SCID mice with non-functional B and T cells over a 4 week CS exposure period, where macrophages accumulated to the same extent as WT mice. Gene expression analysis by QPCR of isolated immune cell subsets detected increased levels of IL-17A transcript in macrophages, neutrophils and NK/NKT cells in the lungs of CS-exposed mice. In order to further explore the relative contribution of innate immune cellular sources, intracellular IL-17A staining was performed. Here, we demonstrate that CS exposure primes NK, NKT and gammadelta T cells to produce more IL-17A protein and CS alone increased the frequency of IL17+ gammadelta T cells in the lung, whereas IL-17A protein was not detected in macrophages and neutrophils. Our data suggest that activation of innate cellular sources of IL-17A is an essential mediator of macrophage accumulation in CS-exposed lungs. Targeting non-conventional T cell sources of IL-17A may offer an alternative strategy to reduce pathogenic macrophages in COPD.

AB - Cigarette smoke (CS) is the major cause of chronic obstructive pulmonary disease (COPD). Interleukin-17A (IL-17A) is a pivotal cytokine that regulates lung immunity and inflammation. The aim of this study was to investigate how IL-17A regulates CS-induced lung inflammation in vivo . IL-17A KO mice and neutralisation of IL-17A in WT mice reduced macrophage and neutrophil recruitment and CCL2, CCL3 and MMP-12 mRNA expression in response to acute CS exposure. IL-17A expression was increased in NOD SCID mice with non-functional B and T cells over a 4 week CS exposure period, where macrophages accumulated to the same extent as WT mice. Gene expression analysis by QPCR of isolated immune cell subsets detected increased levels of IL-17A transcript in macrophages, neutrophils and NK/NKT cells in the lungs of CS-exposed mice. In order to further explore the relative contribution of innate immune cellular sources, intracellular IL-17A staining was performed. Here, we demonstrate that CS exposure primes NK, NKT and gammadelta T cells to produce more IL-17A protein and CS alone increased the frequency of IL17+ gammadelta T cells in the lung, whereas IL-17A protein was not detected in macrophages and neutrophils. Our data suggest that activation of innate cellular sources of IL-17A is an essential mediator of macrophage accumulation in CS-exposed lungs. Targeting non-conventional T cell sources of IL-17A may offer an alternative strategy to reduce pathogenic macrophages in COPD.

UR - http://www.clinsci.org/content/ppclinsci/129/9/785.full.pdf

U2 - 10.1042/CS20140703

DO - 10.1042/CS20140703

M3 - Article

VL - 129

SP - 785

EP - 796

JO - Clinical Science and Molecular Medicine

JF - Clinical Science and Molecular Medicine

SN - 0009-9287

IS - 9

ER -