Serum amyloid P: a systemic regulator of the innate immune response

Abstract

The pentraxin SAP reduces neutrophil adhesion to ECM proteins, inhibits the differentiation of monocytes into fibrocytes, attenuates profibrotic macrophages, activates the complement pathway, and promotes phagocytosis of cell debris. Together, these effects of SAP regulate key aspects of inflammation and set a threshold for immune cell activation. Here, we present a review of SAP biology with an emphasis on SAP receptor interactions and how the effect of SAP on monocytes and macrophages has been explored to develop this protein as a therapeutic for renal and lung injuries. We also discuss how there remain many unanswered questions about the role of SAP in innate immunity.

Keywords: Fcγ receptors; fibrocyte differentiation; fibrosis; macrophage polarization; neutrophil adhesion; phagocytosis.

Figure 1

SAP inhibits neutrophil recruitment. (A) In response to chemoattractants, such as CXCL8, neutrophils begin to migrate into the tissue in a process that involves neutrophil rolling, arrest, and extravasation. All of these steps are mediated by adhesion receptors on the endothelial cells and on neutrophils. (B) In the presence of high levels of SAP, neutrophil recruitment to the tissue is reduced, as SAP‐induced IL‐10 inhibits the secretion of CXCL8. SAP also reduces neutrophil adhesion by preventing L‐selectin binding to adhesion receptors on endothelial cells. SAP may further affect neutrophil adhesion by regulating adhesion receptors on neutrophils by inside‐out signaling via FcγRs. In addition, SAP reduces neutrophil migration by inhibiting neutrophil spreading and elastase activity.

Figure 2

SAP inhibits fibrocyte formation. (A) When SAP is present in the tissue, as is the case in early inflammation, SAP binds to FcγRI to inhibit fibrocyte differentiation. Deletion of the FcγRI or the FcRγ significantly reduces the inhibitory effect of SAP. (B) At late stages of inflammation, when SAP levels are low, monocytes differentiate into fibroblast‐like cells called fibrocytes. Fibrocytes then secrete ECM components, such as collagen and extracellular‐modifying enzymes, to restore the architecture of the damaged tissue.

Figure 3

SAP inhibits profibrotic macrophages in mice. SAP attenuates profibrotic macrophages in renal and pulmonary injuries of mice in an FcRγ‐mediated manner. SAP also opsonizes cell debris to promote their removal by macrophages.