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Serum amyloid P inhibits fibrosis through Fc gamma R-dependent monocyte-macrophage regulation in vivo
Ana P Castaño1, Shuei-Liong Lin, Teresa Surowy
1Laboratory of Inflammation Research, Harvard Institutes of Medicine, 4 Blackfan Circle, Boston, MA 02115, USA.
Abstract:
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 Fc gamma 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 Fc gamma 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 Fc gamma receptors and interleukin-10 expression. These studies uncover previously unidentified roles for Fc gamma receptors in sterile inflammation and highlight serum amyloid P as a potential antifibrotic therapy through local generation of interleukin-10.
Insights
Therapeutic administration of human serum amyloid P (SAP) inhibits kidney fibrosis progression in mice. This antifibrotic effect is mediated by Fc gamma receptors, inflammatory monocytes, and macrophages, highlighting SAP as a potential therapy.
Area of Science:
- Immunology
- Nephrology
- Molecular Biology
Background:
- Chronic organ fibrosis is driven by innate inflammatory cell activation.
- New therapies targeting chronic inflammation and fibrosis are critically needed.
- Serum amyloid P (SAP) is a pattern recognition receptor involved in immune responses.
Purpose of the Study:
- To investigate the antifibrotic potential of human serum amyloid P (SAP) in kidney fibrosis.
- To elucidate the mechanisms underlying SAP-mediated inhibition of fibrosis, including the role of Fc gamma receptors and inflammatory cells.
Main Methods:
- Therapeutic administration of human SAP in a mouse model of kidney fibrosis.
- In vitro and in vivo assessment of inflammatory cell populations (monocytes, macrophages, fibrocytes).
- Analysis of SAP binding to cell debris and its effect on Fc gamma receptor signaling and interleukin-10 expression.
Main Results:
- Human SAP significantly inhibited kidney fibrosis progression in mice.
- SAP-mediated inhibition was dependent on activating Fc gamma receptors, inflammatory monocytes, and macrophages.
- SAP binding to cell debris suppressed inflammatory monocytes and kidney macrophages, linked to interleukin-10 expression.
Conclusions:
- Human SAP demonstrates significant antifibrotic effects in the kidney.
- Fc gamma receptors play a crucial role in SAP-mediated sterile inflammation and fibrosis suppression.
- Serum amyloid P represents a promising therapeutic candidate for treating fibrotic kidney disease.
