Distinct Fcγ Receptors Mediate the Effect of Serum Amyloid P on Neutrophil Adhesion and Fibrocyte Differentiation

The plasma protein serum amyloid P (SAP) reduces neutrophil adhesion, inhibits the differentiation of monocytes into fibroblast-like cells called fibrocytes, and promotes phagocytosis of cell debris by macrophages. Together, these effects of SAP reduce key aspects of inflammation and fibrosis, and SAP injections improve lung function in pulmonary fibrosis patients. SAP functions are mediated, in part, by Fc gamma Rs, but the contribution of each Fc gamma R is not fully understood. We found that aa Q55 and E126 in human SAP affect human fibrocyte differentiation and SAP binding to Fc gamma RI. E126, K130, and Q128 affect neutrophil adhesion and SAP affinity for Fc gamma RIIa. Q128 also affects phagocytosis by macrophages and SAP affinity for Fc gamma RI. All the identified functionally significant amino acids in SAP form a binding site that is distinct from the previously described SAP-Fc gamma RIIa binding site. Blocking Fc gamma RI with an IgG-blocking Ab reduces the SAP effect on fibrocyte differentiation, and ligating Fc gamma RIIa with Abs reduces neutrophil adhesion. Together, these results suggest that SAP binds to Fc gamma RI on monocytes to inhibit fibrocyte differentiation, and binds to Fc gamma RIIa on neutrophils to reduce neutrophil adhesion.