Research ArticleFibrosis

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

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Science Translational Medicine  04 Nov 2009:
Vol. 1, Issue 5, pp. 5ra13
DOI: 10.1126/scitranslmed.3000111

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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.

Footnotes

  • * These authors contributed equally to this work.

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