The Development of Serum Amyloid P as a Possible Therapeutic

Abstract

Pentraxins such as serum amyloid P (SAP; also known as PTX2) regulate several aspects of the innate immune system. SAP inhibits the differentiation of monocyte-derived fibroblast-like cells called fibrocytes, promotes the formation of immuno-regulatory macrophages, and inhibits neutrophil adhesion to extracellular matrix proteins. In this minireview, we describe how these effects of SAP have led to its possible use as a therapeutic, and how modulating SAP effects might be used for other therapeutics. Fibrosing diseases such as pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis are associated with 30-45% of deaths in the US. Fibrosis involves both fibrocyte differentiation and profibrotic macrophage differentiation, and possibly because SAP inhibits both of these processes, in 9 different animal models, SAP inhibited fibrosis. In Phase 1B and Phase 2 clinical trials, SAP injections reduced the decline in lung function in pulmonary fibrosis patients, and in a small Phase 2 trial SAP injections reduced fibrosis in myelofibrosis patients. Acute respiratory distress syndrome/ acute lung injury (ARDS/ALI) involves the accumulation of neutrophils in the lungs, and possibly because SAP inhibits neutrophil adhesion, SAP injections reduced the severity of ARDS in an animal model. Conversely, depleting SAP is a potential therapeutic for amyloidosis, topically removing SAP from wound fluid speeds wound healing in animal models, and blocking SAP binding to one of its receptors makes cultured macrophages more aggressive toward tuberculosis bacteria. These results suggest that modulating pentraxin signaling might be useful for a variety of diseases.

Keywords: fibrocyte; fibrosis; macrophage; pentraxin; pulmonary fbrosis; serum amyloid P component (SAP).

Figure 1

SAP regulates multiple aspects of immune responses. Some of the known effects of SAP are shown clockwise from top: SAP inhibits neutrophil adhesion to extracellular matrix and inhibits neutrophil movement into tissues. SAP binds to FcγR and DC-SIGN to inhibit monocyte to fibrocyte differentiation. SAP also binds multiple plasma proteins such as the complement component C1q and mannose-binding lectin (MBL) to promote phagocytosis of bacteria and regulate macrophage differentiation. SAP opsonizes bacteria and cell debris to promote removal by macrophages, and binds amyloid deposits. Finally, SAP promotes immuno-regulatory, and M1 phagocytic macrophages.