Synergy between serum amyloid A and secretory phospholipase A2

Abstract

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.

Structural Basis for Vital Function and Malfunction of Serum Amyloid A: an Acute-Phase Protein that Wears Hydrophobicity on Its Sleeve

“…The SAA fold has been highly evolutionarily conserved since the Cambrian period, long before the emergence of HDL, suggesting that the primordial role of SAA does not involve HDL binding. Rather, it probably involves sequestration and transport of lipids, such as cell membrane debris, to avoid lipotoxicity at the sites of injury and facilitate tissue healing [ 78 •]. If verified in vivo, this role explains how the rapid and massive generation of SAA hours after the onset of acute injury, infection, or inflammation has benefitted the host survival throughout evolution.…”

“…However, the levels of albumin, which normally sequesters most circulating NEFA and lyso-phospholipids, decrease in acute inflammation. Moreover, albumin’s affinity for NEFA decreases at acidic pH at the inflammation sites ([ 78 •] and references therein), causing potential accumulation of toxic lipids. Can SAA compensate for albumin deficiency and protect the inflammation sites from lipotoxicity?…”

“…First, SAA solubilizes phospholipids to generate nanoparticles that provide substrates for sPLA 2 ; second, SAA sequesters its water-insoluble products, lyso-phospholipids, and NEFA, thereby removing the rate-limiting step of lipolysis [ 78 •]. Moreover, unlike albumin, the binding affinity of SAA for NEFA remains invariant in a broad pH range, surpassing that of albumin at acidic conditions found at the inflammation sites [ 78 •], while the local SAA levels at these sites increase even more than its systemic levels. Together, the results suggest that SAA can help compensate for albumin’s deficiency and substantially contribute to removal of toxic lipid from the inflammation sites.…”

Biological Characterization of Commercial Recombinantly Expressed Immunomodulating Proteins Contaminated with Bacterial Products in the Year 2020: The SAA3 Case

“…Almost simultaneously, Cheng et al showed that recombinant SAA1 is able to bind LPS in a dose-dependent manner, diminishing LPS-induced proinflammatory effects [35]. In fact, SAA1 was shown to bind a variety of ligands, including lysophospholipids [49,50], HDL and other lipoproteins [51,52], cholesterol [53] and retinol [54,55].…”

Metabolic Programming of Macrophages: Implications in the Pathogenesis of Granulomatous Disease

“…In this study, SAA was shown to promote chronic inflammation in sarcoid granulomas via TLR2 signaling and activation of NF-κB, as well as cytokine production (224). Contrastingly, recent evidence suggests that during inflammation, SAA acts synergistically with secretory phospholipase-A to remove cell membrane debris, which suggests a partial involvement in anti-inflammatory repair processes (225). Interestingly, SAA has also been suggested to be responsible for the low HDL cholesterol and apoA1 levels observed in patients with active sarcoidosis (226, 227), which has been linked to an increased risk of atherosclerosis in sarcoidosis patients (219).…”