Serum Amyloid A: A Double-Edged Sword in Health and Disease

Despite more than fifty years since its discovery in the 1970s, Serum Amyloid A (SAA)’s true biological functions remain enigmatic. The research so far has primarily associated SAA with chronic inflammatory conditions such as cardiovascular disease, obesity, and type 2 diabetes; its role in acute inflammation is less understood. Unlike the modest elevations observed in chronic conditions, SAA levels surge dramatically during acute inflammatory responses. Notably, approximately 2.5% of hepatic protein synthesis is devoted to SAA production during acute inflammation—despite the high energy demands required for synthesizing pro-inflammatory cytokines and immune cell activation—leaving its precise necessity unclear. Elucidating SAA’s physiological role in acute inflammation is crucial to determine the therapeutic potential of SAA inhibition for chronic inflammatory diseases, such as atherosclerosis and abdominal aortic aneurysms. The evidence suggests that SAA may play a protective role in acute inflammation, positioning it as a “double-edged sword”: detrimental in chronic inflammation, yet potentially beneficial in acute settings. This review explores the divergent roles of SAA in chronic versus acute inflammation, proposing that while SAA inhibition could offer therapeutic benefits for chronic conditions, it might pose risks during acute inflammation. As the primary transporter of SAA in circulation, high-density lipoprotein (HDL) has been shown to become dysfunctional in chronic inflammation, at least partly due to SAA’s effects. However, we propose that SAA may confer functional properties to HDL during acute inflammatory states, such as sepsis, thereby highlighting the context-dependent nature of its impact.