Endogenous Acute Phase Serum Amyloid A Lacks Pro-Inflammatory Activity, Contrasting the Two Recombinant Variants That Activate Human Neutrophils through Different Receptors.

Karin Christenson,Johan Bylund,Sofie Ahlin,Lena Björkman,Maja Olsson,Anna Karlsson,Kajsa Sjöholm

doi:10.3389/fimmu.2013.00092

Abstract

Most notable among the acute phase proteins is serum amyloid A (SAA), levels of which can increase 1000-fold during infections, aseptic inflammation, and/or trauma. Chronically elevated SAA levels are associated with a wide variety of pathological conditions, including obesity and rheumatic diseases. Using a recombinant hybrid of the two human SAA isoforms (SAA1 and 2) that does not exist in vivo, numerous in vitro studies have given rise to the notion that acute phase SAA is a pro-inflammatory molecule with cytokine-like properties. It is however unclear whether endogenous acute phase SAA per se mediates pro-inflammatory effects. We tested this in samples from patients with inflammatory arthritis and in a transgenic mouse model that expresses human SAA1. Endogenous human SAA did not drive production of pro-inflammatory IL-8/KC in either of these settings. Human neutrophils derived from arthritis patients displayed no signs of activation, despite being exposed to severely elevated SAA levels in circulation, and SAA-rich sera also failed to activate cells in vitro. In contrast, two recombinant SAA variants (the hybrid SAA and SAA1) both activated human neutrophils, inducing L-selectin shedding, production of reactive oxygen species, and production of IL-8. The hybrid SAA was approximately 100-fold more potent than recombinant SAA1. Recombinant hybrid SAA and SAA1 activated neutrophils through different receptors, with recombinant SAA1 being a ligand for formyl peptide receptor 2 (FPR2). We conclude that even though recombinant SAAs can be valuable tools for studying neutrophil activation, they do not reflect the nature of the endogenous protein.

Highlights

Serum amyloid A (SAA) is one of the most prominent acute phase proteins in the body and the levels in plasma can rise 1000-fold in response to inflammation, infection, or tissue injury
The recombinant SAA1 (rSAA1)-induced effects were mediated by formyl peptide receptor 2 (FPR2), whereas this receptor did not mediate neutrophil responses to recombinant SAA hybrid (rSAAh)
For a number of other cytokines we found that, some were elevated in the patient group as a whole, there was a remarkable lack of correlation between SAA concentrations and levels of inflammatory cytokines in patient plasma (Figure 3)

Summary

Introduction

Serum amyloid A (SAA) is one of the most prominent acute phase proteins in the body and the levels in plasma can rise 1000-fold in response to inflammation, infection, or tissue injury. Using purified endogenous acute phase SAA, as well as blood samples from rheumatic patients with elevated levels of endogenous SAA, we found the endogenous SAA to be remarkably inert, whereas rSAAh potently activated human phagocytes (Bjorkman et al, 2010).

Results

Conclusion