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

Abstract

Rationale: 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. Objectives: To determine whether SAA causes neutrophilic inflammation by IL-17A-dependent mechanisms. Methods: 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. Measurements and Main Results: SAA mRNA expression was positively associated with tissue neutrophils in COPD (P , 0.05). SAA predominately promoted expression of the T H 17 polarizing cytokine IL-6, which was opposed by 15-epi-lipoxin A 4 , a counter-regulatory mediator, and ALX/FPR2 ligand. SAA-induced inflammation was markedly reduced by a neutralizing antibody to IL-17A in vivo. Chronic lung diseases, such as chronic obstructive pulmonary disease (COPD) and severe asthma, are characterized by an exaggerated inflammatory profile involving accumulation of neutrophils with disease progression (1). Neutrophilic inflammation increases with COPD severity despite escalating use of glucocorticosteroids (2, 3), which contributes to excessive proteinase release and host tissue damage (4). Respiratory infections also trigger acute exacerbations of COPD (AECOPD), where airway neutrophilia increases with severity (5). AECOPDs have a major impact because they lead to impaired health-related quality of life (6) and a more rapid decline in lung function (7). We have previously shown that circulating serum amyloid A (SAA) levels acutely rise during AECOPD, where its levels were predictive of event severity (8). Furthermore, we have demonstrated elevated SAA immunoreactivity in the submucosa of COPD lung sections in close proximity to the basal epithelium and show a positive correlation between secreted SAA and the neutrophil activation marker, neutrophil elastase (9). SAA promotes expression of inflammatory mediators and neutrophil chemotaxis and survival by the ALX-FPR2 receptor in a manner that is opposed by the endogenous proresolving lipid mediator lipoxin A 4 (LXA 4 ) (9-12).SAA is also a potent endogenous ligand that stimulates expression of T H 17 polarizing mediators (13,14), and influences in vitro T H 17 differentiation of CD4 1 T cells (15). IL-17A promotes inflammation by coordinating granulopoiesis and neutrophil mobilization through its regulation of leukocyte growth factors and cytokines. IL-17A is particularly central to lung immunity because innate host defenses to respiratory pathogens are compromised in mice lacking this cytokine or its receptor (IL-17RA), leading to reduced neutrophil recruitment and increased bacterial burden (16,17). An increase in IL-17A 1 im...

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“…SAA is a potent chemotactic factor that mediates migration of leukocytes [14] and can also promote expression of proinflammatory mediators under in vitro [25] and in vivo conditions [12]. We have previously shown that SAA induces a proinflammatory macrophage phenotype [26] that stimulated acute neutrophilic lung inflammation in an Fpr2-dependent manner [16].…”

“…On day 7, mice were culled by intraperitoneal overdose of sodium pentobarbitone. Bronchoalveolar lavage (BAL) was performed via tracheotomy and total/differential BAL cell counts were determined as previously described [16]. Lung was perfused with ice-cold PBS to remove excess blood.…”

“…Single-cell suspension preparation and flow cytometric analysis were performed as previously described [16]. Inhibition of non-antigen binding of immunoglobulins to Fc receptors was performed using a rat anti-mouse CD16/CD32 antibody (BD Biosciences).…”

“…SAA is also a functional agonist for the formyl peptide receptor 2/lipoxin A 4 (LXA 4 ) receptor (Fpr2/ALX) where it stimulates leukocyte chemotaxis [14]. Furthermore, we have recently shown that local lung challenge with recombinant SAA potently stimulates neutrophilic inflammation via IL-17A-dependent mechanisms [15,16]. SAA can also promote neutrophil survival by suppressing the apoptotic machinery through activation of ERK and PI3K/Akt signaling pathways [17].…”

Microbiota Promotes Chronic Pulmonary Inflammation by Enhancing IL-17A and Autoantibodies

“…Both autoimmune mechanisms and IL-17 (31,(46)(47)(48)(49)(50)(51)(52)(53)(54) In an attempt to assess whether the altered microbiota in disease could directly enhance IL-17A responses, we performed a transfer experiment. Antibiotic treated mice were challenged with LPS/elastase on day 0,7 and 21.…”