Serum Amyloid A Promotes Lung Neutrophilia by Increasing IL-17A Levels in the Mucosa and γδ T Cells

• Published in: American journal of respiratory and critical care medicine Vol. 188; no. 2; pp. 179 - 186
• Main Authors: ANTHONY, Desiree, HUEI JIUNN SEOW, UDDIN, Mohib, THOMPSON, Michelle, DOUSHA, Lovisa, VLAHOS, Ross, IRVING, Louis B, LEVY, Bruce D, ANDERSON, Gary P, BOZINOVSKI, Steven
• Format: Journal Article
• Language: English
• Published: New York, NY American Thoracic Society 15.07.2013
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Bronchoalveolar Lavage Fluid - chemistry; Cells, Cultured; Chronic obstructive pulmonary disease, asthma; Disease Models, Animal; Flow Cytometry; Humans; Immunity, Innate; Immunohistochemistry; Inflammation - immunology; Intensive care medicine; Interleukin-17 - blood; Interleukin-17 - immunology; Lung - cytology; Lung - immunology; Medical sciences; Mice; Neutrophil Infiltration - physiology; Neutrophils - immunology; Neutrophils - pathology; Pneumology; Pulmonary Disease, Chronic Obstructive - blood; Pulmonary Disease, Chronic Obstructive - immunology; Respiratory Mucosa - immunology; Serum Amyloid A Protein - analysis; Serum Amyloid A Protein - immunology; T-Lymphocyte Subsets - immunology; Lung disease; Intensive care; Respiratory disease; Mucosa; Lung; Cytokine; Granulocyte; Natural immunity; Inflammation; innate immunity; T-Lymphocyte; Bronchus disease; Serum; Chronic obstructive pulmonary disease; Neutrophil; neutrophils; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.201211-2139OC

Neutrophilic 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. To determine whether SAA causes neutrophilic inflammation by IL-17A-dependent mechanisms. The 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. SAA 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. The 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.