Serum amyloid A3 is required for normal weight and immunometabolic function in mice.

Jennifer L Ather,Matthew E Poynter,G William Wong

doi:10.1371/journal.pone.0192352

Abstract

Serum amyloid A (SAA) is an apolipoprotein that is robustly upregulated in numerous inflammatory diseases and has been implicated as a candidate pro-inflammatory mediator. However, studies comparing endogenous SAAs and recombinant forms of the acute phase protein have generated conflicting data on the function of SAA in immunity. We generated SAA3 knockout mice to evaluate the contribution of SAA3 to immune-mediated disease, and found that mice lacking SAA3 develop adult-onset obesity and metabolic dysfunction along with defects in innate immune development. Mice that lack SAA3 gain more weight, exhibit increased visceral adipose deposition, and develop hepatic steatosis compared to wild-type littermates. Leukocytes from the adipose tissue of SAA3-/- mice express a pro-inflammatory phenotype, and bone marrow derived dendritic cells from mice lacking SAA3 secrete increased levels of IL-1β, IL-6, IL-23, and TNFα in response to LPS compared to cells from wild-type mice. Finally, BMDC lacking SAA3 demonstrate an impaired endotoxin tolerance response and inhibited responses to retinoic acid. Our findings indicate that endogenous SAA3 modulates metabolic and immune homeostasis.

Highlights

Serum amyloid A (SAA), an acute phase lipoprotein, has been studied for decades as a robust biomarker for a wide array of inflammatory and autoimmune disorders [1]
A comparative analysis of organs from wild-type (WT) mice indicated that, as has been previously published [22], the expression of Saa3 is highest in the visceral adipose tissue (VAT) and the lung, with substantially less being expressed in the liver, spleen, and kidney (Fig 1A)
We confirmed the effective elimination of Saa3 expression in our knockout (SAA3-/-) littermates in the same tissues (Fig 1B), and determined that levels of Saa1 and Saa2 were normal in the Visceral adipose tissue (VAT) of SAA3-/- mice (Fig 1C)

Summary

Introduction

Serum amyloid A (SAA), an acute phase lipoprotein, has been studied for decades as a robust biomarker for a wide array of inflammatory and autoimmune disorders [1]. Multiple isoforms of this protein have been identified, including: SAA1 and 2, which are highly homologous and predominantly produced by the liver; SAA3, an acutely expressed isoform produced in nonprimate mammals; and SAA4, which is constitutively expressed and does not increase in response to infection or injury [2].

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