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Serum Amyloid P Inhibits Fibrosis Through FcγR-Dependent Monocyte-Macrophage Regulation in Vivo

The fibrosis that occus in kidney after tissue injury can be inhibited by serum amyloid protein, which stimulates the cytokine interleukin 10. Suppressing Fibrosis When it comes to repairing damaged tissues or organs, there can be too much of a good thing. Although sometimes the body’s natural repair processes lead to complete restoration of normal tissue after an injury, at other times these processes continue unrestrained, leading to the replacement of normal tissue with fibrous scars—potentially causing organ failure and death. Such fibrosis is a common underlying feature of a wide variety of diseases, including cirrhosis of the liver, cardiovascular disease, rheumatoid arthritis, and progressive kidney disease. Even though fibroproliferative diseases are a leading cause of death in Western societies, there are currently no therapies that target fibrosis directly. Now, Duffield and colleagues describe a potential antifibrotic therapy for fibrosis of the kidney. The body’s repair processes are triggered by a range of harmful events, such as physical trauma, infections, toxin-induced damage, or an inadequate supply of blood. Tissue repair progresses through several stages, including an inflammatory response with an influx of white blood cells like monocytes, apoptosis and necrosis, the activation of wound-healing myofibroblasts, and the deposition and remodeling of extracellular matrix. When this matrix expands in an apparently uncontrolled manner, fibrous scars—consisting primarily of collagen—are formed. Compounds that inhibit the formation of these scars would be welcome tools for treating fibroproliferative diseases. Duffield’s group sought to determine whether serum amyloid P (SAP)—a protein previously shown to inhibit fibrosis in the lung and heart—might also suppress fibrosis in the kidney. SAP can bind ligands on the surface of apoptotic cells as well as Fcγ receptors on certain immune cells, and binding of SAP to the apoptotic cell ligands induces Fcγ receptor–dependent phagocytosis. These observations suggest that SAP might localize to sites of injury, aiding in the removal of wounded tissue. Duffield’s team showed that administration of human SAP to mice with experimentally induced kidney injury markedly decreased fibrosis. The SAP was recruited to the injured kidney where it was associated with dead cells. In the lung and heart, SAP appears to act by inhibiting fibrocytes, which directly produce collagen matrix. In the kidney, however, fibrocytes do not participate in fibrosis. Instead, the researchers determined, kidney fibrosis in mice depends on inflammatory monocytes and macrophages. SAP binds to and suppresses these cells, an effect that depends on expression of the anti-inflammatory cytokine IL-10 and regulated binding to Fcγ receptors, which are expressed on monocytes and macrophages. Given that a form of human SAP is now being tested in a phase 1 clinical trial in healthy volunteers, we may soon know whether it suppresses fibrotic disease in humans. New therapies that target chronic inflammation with fibrosis are urgently required. Increasing evidence points to innate activation of inflammatory cells in driving chronic organ fibrosis. Serum amyloid P is a naturally circulating soluble pattern recognition receptor, a member of the family of pentraxin proteins. It links danger-associated molecular pattern recognition to Fcγ receptor–mediated phagocytosis. Here we show that fibrosis progression in the mouse kidney is significantly inhibited by therapeutic administration of human serum amyloid P, regulated by activating Fcγ receptors, and dependent on inflammatory monocytes and macrophages, but not fibrocytes. Human serum amyloid P–mediated inhibition of mouse kidney fibrosis correlated with specific binding of human serum amyloid P to cell debris and with subsequent suppression of inflammatory monocytes and kidney macrophages in vitro and in vivo, and was dependent on regulated binding to activating Fcγ receptors and interleukin-10 expression. These studies uncover previously unidentified roles for Fcγ receptors in sterile inflammation and highlight serum amyloid P as a potential antifibrotic therapy through local generation of interleukin-10.