Serum Amyloid A Activates the NLRP3 Inflammasome and Promotes Th17 Allergic Asthma in Mice

Abstract

Interleukin (IL)-1β is a cytokine critical to several inflammatory diseases in which pathogenic TH17 responses are implicated. Activation of the NLRP3 inflammasome by microbial and environmental stimuli can enable the caspase-1 dependent processing and secretion of IL-1β. The acute phase protein serum amyloid A (SAA) is highly induced during inflammatory responses, wherein it participates in systemic modulation of innate and adaptive immune responses. Elevated levels of IL-1β, SAA, and IL-17 are present in subjects with severe allergic asthma, yet the mechanistic relationship between these mediators has yet to be identified. Herein, we demonstrate that Saa3 is expressed in the lung of mice exposed to several mixed Th2/Th17-polarizing allergic sensitization regimens. SAA instillation into the lungs elicits robust TLR2-, MyD88-, and IL-1-dependent pulmonary neutrophilic inflammation. Furthermore, SAA drives production of IL-1α, IL-1β, IL-6, IL-23, and PGE2, causes dendritic cell maturation, and requires TLR2, MyD88, and the NLRP3 inflammasome for secretion of IL-1β by dendritic cells and macrophages. CD4+ T cells polyclonally stimulated in the presence of conditioned media from SAA-exposed dendritic cells produced IL-17 and the capacity of polyclonally-stimulated splenocytes to secrete IL-17 is dependent upon IL-1, TLR2, and the NLRP3 inflammasome. Additionally, in a model of allergic airway inflammation, administration of SAA to the lungs functions as an adjuvant to sensitize mice to inhaled ovalbumin, resulting in leukocyte influx after antigen challenge and a predominance of IL-17 production from restimulated splenocytes that is dependent upon IL-1 receptor signaling.

Serum amyloid A links endotoxaemia to weight gain and insulin resistance in mice

“…When not associated with HDL, SAA is a stimulus for the production of cytokines, reactive oxygen species and NO [13][14][15]31]. SAA is also able to activate the inflammasome pathway, considered a mediator of the innate and adaptive immune system [32,33]. Furthermore, SAA is induced by hypoxia [22], a common event in fat expansion.…”

IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

“…We used gene-deficient mice and evaluated the role of IL-17A in CCl 4 -induced acute and chronic injury and HSC activation. IL-17A/IL-17RA signaling plays a critical role in autoimmune diseases such as asthma, arthritis, ulcerative colitis, and Crohn's disease (30)(31)(32)(33). IL-17A is involved in neutrophil recruitment and angiogenesis (34), and IL-17A expression is partially dependent on IL-1 and IL-23 signaling (8,35).…”

Shifting of Immune Responsiveness to House Dust Mite by Influenza A Infection: Genomic Insights

“…Saa3, is a major acute-phase protein that can act as a chemoattractant for phagocytes (35) and recently was shown to promote Th17-mediated allergic asthma through the activation of the NLRP3 inflammasome complex (36). Our data showed that this gene was significantly upregulated following Flu infection, with an additional 2-fold increase following HDM exposure during the EP that was sustained through the LP, where we observed a 5-fold difference in expression level between Flu-and Flu+HDM-treated mice (Tables VI, VII).…”