Research Article: Serum amyloid A3 is required for normal weight and immunometabolic function in mice

Date Published: February 1, 2018

Publisher: Public Library of Science

Author(s): Jennifer L. Ather, Matthew E. Poynter, G. William Wong.


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.

Partial Text

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 non-primate mammals; and SAA4, which is constitutively expressed and does not increase in response to infection or injury [2]. In mice, SAA3 is the primary SAA isoform expressed in epithelial and hematopoietic cells [3], and we have previously demonstrated a rapid increase in Saa3 gene expression in the lung in response to a variety of pro-inflammatory stimuli capable of inducing pulmonary innate and adaptive immune responses [4].

Serum amyloid A has been observed to increase ~1000 fold in the serum in response to a number of infection and injury models [1]. Additionally, tissue-specific expression of Saa3 increases in mice in response to a variety of stimuli [4]. Given its rapid and robust increase under inflammatory and autoimmune conditions, it has long been speculated that SAA is a mediator of the inflammatory process. We and others have published data suggesting this is the case using a commercially available recombinant form of SAA [4, 32, 33]. However, the E. coli-derived recombinant form of SAA that is almost uniformly used by investigators elicits strong pro-inflammatory responses not shared with the endogenous form of SAA [34]. Specifically, whereas recombinant apoSAA promoted neutrophil activation and pro-inflammatory cytokine production, human plasma containing highly elevated levels of SAA displayed neither of those effects. These results imply that further characterization of the differences in pro-inflammatory activities between recombinant and endogenous SAA is warranted. Consequently, our observations suggest that the robust production of SAA3 in response to injury or infection may be an attempt to maintain homeostatic function; that is, that endogenously produced SAA may exert a protective or pro-resolving effect in the immune response.




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