• Desiree Anthony, Huei Jiunn Seow, Mohib Uddin, Michelle Thompson, Lovisa Dousha, Ross Vlahos, Louis B Irving, Bruce D Levy, Gary P Anderson, and Steven Bozinovski.
• Department of Pharmacology and Therapeutics, The University of Melbourne, Parkville, Victoria, Australia.
• Am. J. Respir. Crit. Care Med.. 2013 Jul 15;188(2):179-86.

RationaleNeutrophilic inflammation is an important pathologic feature of chronic obstructive pulmonary disease (COPD) and infectious exacerbations of COPD. Serum amyloid A (SAA) promotes neutrophilic inflammation by its interaction with lung mucosal ALX/FPR2 receptors. However, little is known about how this endogenous mediator regulates IL-17A immunity.ObjectivesTo determine whether SAA causes neutrophilic inflammation by IL-17A-dependent mechanisms.MethodsThe relationship between SAA and neutrophils was investigated in lung sections from patients with COPD and a chronic mouse model of SAA exposure. A neutralizing antibody to IL-17A was used to block SAA responses in vivo, and a cell-sorting strategy was used to identify cellular sources.Measurements And Main ResultsSAA mRNA expression was positively associated with tissue neutrophils in COPD (P < 0.05). SAA predominately promoted expression of the TH17 polarizing cytokine IL-6, which was opposed by 15-epi-lipoxin A4, a counter-regulatory mediator, and ALX/FPR2 ligand. SAA-induced inflammation was markedly reduced by a neutralizing antibody to IL-17A in vivo. Cellular sources of IL-17A induced by SAA include CD4(+) T cells, γδ T cells, and an Epcam(+)CD45(-) population enriched for epithelial cells. SAA promotes expression of IL-17A in γδ T cells and this innate cell proportionally expressed higher levels of IL-17A transcript than CD4(+) T cells or epithelial cells.ConclusionsThe SAA-IL-17A axis represents an important innate defense network that may underlie persistent neutrophilic airway inflammation in COPD and modulating the ALX/FPR2 receptor represents a novel approach to targeting aberrant IL-17A-mediated lung immunity.

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