Synergy between serum amyloid A and secretory phospholipase A₂ suggests a vital role for an ancient protein in lipid clearance

Serum amyloid A (SAA) is an evolutionally conserved enigmatic biomarker of inflammation. In acute inflammation, SAA plasma levels increase ~1,000-fold suggesting a vital beneficial role. SAA increases simultaneously with secretory phospholipase A₂ (sPLA₂), compelling us to determine how SAA influences sPLA₂ hydrolysis of lipoproteins. SAA solubilized phospholipid bilayers to form lipoproteins that provided substrates for sPLA₂. Moreover, SAA sequestered free fatty acids and lysophospholipids to form stable proteolysis-resistant complexes. Unlike albumin, SAA effectively removed free fatty acids under acidic conditions, which characterize inflammation sites. Therefore, SAA solubilized lipid bilayers to generate substrates for sPLA₂ and removed its bioactive products. Consequently, SAA and sPLA₂ can act synergistically to remove cellular membrane debris from the injured sites, which is a prerequisite for tissue healing. We postulate that removal of lipids and their degradation products constitutes a vital primordial role of SAA in innate immunity; this role remains to be tested in vivo.