Abstract
Serum amyloid A (SAA) proteins are a family of acute phase apolipoproteins implicated to directly modulate innate and adaptive immune responses. However, new studies comparing endogenous SAAs and recombinant forms of these proteins have questioned the function of SAA in inflammation and immunity. We generated SAA3 knockout mice to evaluate the contribution of SAA3 to lung development and immune-mediated lung disease. While SAA3 deficiency does not affect the generation of house dust mite-induced allergic asthma, mice lacking SAA3 develop adult-onset obesity, intrinsic airway hyperresponsiveness, increased inflammatory and fibrotic gene expression in the lung, and elevated levels of lung citrullinated proteins. Polyclonally stimulated CD4+ T cells from SAA3−/− mice exhibit impaired glycolytic activity, decreased TH2 and TH1 cytokine secretion, and elevated IL-17A production compared to wild type cells. Polyclonally stimulated CD8+ T cells from SAA3−/− mice also exhibit impaired glycolytic activity as well as a diminished capacity to produce IL-2 and IFNγ. Finally, SAA3−/− mice demonstrate increased mortality in response to H1N1 influenza infection, along with higher copy number of viral RNAs in the lung, a lack of CD8+ T cell IFNγ secretion, and decreased flu-specific antibodies. Our findings indicate that endogenous SAA3 regulates lung development and homeostasis, and is required for protection against H1N1 influenza infection.
Highlights
Serum amyloid A (SAA) proteins were first characterized as components of amyloid fibril deposits in amyloidosis, and later as lipoproteins bound to HDL in human plasma[1,2,3]
SAA3−/− mice had higher expression of interleukin-6 (Il6) and tumor necrosis factor alpha (Tnfa) in the lung, while the expression of interleukin-22 (Il22) and the mucin-associated gene calcium-activated chloride channel 1 (Clca1) were significantly reduced in SAA3−/− mice compared to wild type littermates (Fig. 1B)
The exacerbated responses in RN are significantly correlated to weight in both males and females (Fig. 1D), which raised the question of whether there are developmental differences in the lungs of the SAA3−/− mice that are independent of obesity
Summary
Serum amyloid A (SAA) proteins were first characterized as components of amyloid fibril deposits in amyloidosis, and later as lipoproteins bound to HDL in human plasma[1,2,3]. SAA4, called C-SAA, is constitutively expressed and does not increase in response to infection or injury[7]. SAA3 is the predominant isoform expressed in mouse epithelial and hematopoietic cells[8], and our previous work has demonstrated a rapid increase in Saa[3] gene expression in the lung in response to a variety of stimuli that induce innate and adaptive immune responses[9,10]. Inhibition of IL-17A signaling in mouse models of H1N1 influenza decreases neutrophil recruitment and ameliorates influenza-associated lung injury[25,26]. We have generated a mouse lacking SAA310 that, instead of showing decreased proinflammatory responses, exhibits adult-onset obesity, abnormal lung development and intrinsic airway hyperresponsiveness. Lack of SAA3 leads to increased innate proinflammatory responses and altered CD4+ and CD8+ T cell cytokine expression. Mice lacking SAA3 have decreased survival in response to H1N1 influenza infection
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