Synergy between serum amyloid A and secretory phospholipase A2

Serum amyloid A (SAA) is an evolutionally conserved enigmatic biomarker of inflammation. In acute inflammation, SAA plasma levels increase ~1,000 fold, suggesting that this protein family has 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 injured sites, which is a prerequisite for tissue healing. We postulate that the 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. Cell boundaries are made up of fatty substances known as lipids. When cells get severely damaged, their lipid membranes break apart. These broken fragments of membrane become highly toxic, and must be removed as soon as possible to allow the tissue to heal. A small protein called serum amyloid A, SAA for short, was recently proposed to play a pivotal role in this process. In humans, SAA levels in the blood rapidly spike to over a thousand times their normal level following inflammation, injury or infection. Combined with the fact SAA has been conserved for over 500 million years, this suggests that SAA must be important for survival. But, it is not entirely clear how this protein works. One clue for how SAA works is its relationship to another ancient protein called secretory phospholipase A2. This protein, also known as sPLA2, is part of a big family of enzymes that break down lipids in the cell membrane. Notably, sPLA2 levels rise at the same time and place as SAA during inflammation. This led Jayaraman et al. to ask whether SAA and sPLA2 might be working together to clean up the cell membrane debris. To find out, Jayaraman et al. mixed mouse SAA with vesicles of membrane lipids, and then added sPLA2. This revealed that SAA reshapes the lipid membrane into smaller ‘nanoparticles’ with tightly curved surfaces that are easier for sPLA2 to break d