Serum Amyloid A3 is required for normal lung development and survival following influenza infection

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.

Soluble pattern recognition molecules: Guardians and regulators of homeostasis at airway mucosal surfaces

“…Moreover, there is a strong correlation between elevated blood as well as sputum SAA levels and asthma prevalence and/or allergic rhinitis and disease severity [23,24,212]. As described above, the ability of SAA1 to adopt different oligomeric states (monomers and oligomers) [202] or to transport retinols and related molecules [187,188] might serve to scavenge and sequester essential vitamins (or even nutrients) to deter pathogen growth at mucosal surfaces [215] and may thus have important functional implications for promoting local inflammation. Considering that SAA is increased in allergic asthma [23,24], it remains to be established whether SAA functions as an adjuvant and/or interacts directly with environmental airborne proteins to promote allergic sensitization.…”

Novel biomarkers for the prediction of COVID-19 progression a retrospective, multi-center cohort study

“…Serum amyloid A (SAA) is an acute-phase protein during infection and inflammation [21,22]. Emerging evidence showed that SAA could be a potential marker for virus infection, such as Epstein-Barr virus [23], cytomegalovirus infection [24], hepatitis C virus [25], as well as influenza infection [26]. These aforementioned data have suggested that SAA could be an important biomarker in virus infection.…”

Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

“…Whether SAA is not just a marker but also an active participant in disease is intensely investigated, and numerous, sometimes conflicting, functions have been ascribed to this mysterious protein. The current consensus is that SAA modulates adaptive and innate immunity and mediates lipid transport during inflammation [ 1 •, 2 , 13 ].…”