Balancing inflammation: the specific roles of serum amyloid A proteins in sterile and infectious diseases

Serum Amyloid A (SAA) proteins are acute-phase reactants with critical roles in sterile and bacterial inflammation. Through <i>in vitro</i> and <i>in vivo</i> experiments, we demonstrate that SAA proteins amplify cytokine and chemokine responses during sterile inflammation and enhance bacterial clearance in infectious conditions. Mechanistically, SAA proteins augment NF-κB signaling, driving pro and anti-inflammatory mediator production. <i>SAA^-/-</i> mice carrying a deletion of the <i>Saa1</i>, <i>Saa2</i>, <i>Saa3</i>, and <i>Saa4</i> serum amyloid A genes have better survival rates in sterile sepsis but are more prone to bacterial sepsis than their <i>SAA^+/+</i> counterparts, emphasizing their dual functionality in immune regulation. Overexpression of <i>Saa1</i>, <i>Saa2</i>, <i>Saa3</i>, and <i>Saa4</i> in macrophages enhances NF-κB-mediated pro-inflammatory cytokine production and bacterial clearance during infection. Together, our results show that SAA proteins are key modulators of inflammation, with distinct mechanisms tailored to sterile and infectious contexts.