Editors' ChoiceFIBROSIS

Battle scars: SAP and CRP

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Science Translational Medicine  08 Jul 2015:
Vol. 7, Issue 295, pp. 295ec116
DOI: 10.1126/scitranslmed.aac8112

Forty-five percent of deaths in the United States are linked to fibrosis—the formation of scars on internal organs. Two proteins found in the blood, serum amyloid protein (SAP) and C-reactive protein (CRP), have opposite effects on fibrosis, despite extremely similar amino acid sequences and propensities to bind the same Fcγ receptors. Cox et al. reasoned that sugar groups added to SAP but not CRP after translation of the gene into protein might contribute to determining their divergent effects.

The team used in vitro culture of mouse and human macrophages to demonstrate that, contrary to long-held beliefs, binding to Fcγ receptors was required for the proinflammatory behavior of CRP, but not for the anti-inflammatory and antifibrotic behavior of SAP. Enzymatic removal of the posttranslational sugar groups abrogated these behaviors of SAP, whereas adding the sugar groups using genetic modifications made CRP behave like SAP. Because the immune cell surface receptor DC-SIGN has been shown to bind other glycosylated proteins, the team set out to determine whether this receptor was involved in immune cell distinction between SAP and CRP. SAP and glycosylated CRP, but not native CRP, were able to bind to DC-SIGN, and immune cells from mice lacking DC-SIGN did not experience the antifibrotic effects of SAP. Last, systemic administration of a synthetic compound that mimics the actions of SAP by binding to DC-SIGN ameliorated drug-induced lung inflammation and fibrosis in mice. This effect required the anti-inflammatory cytokine IL-10. Interestingly, the cells that were responsible for expression of DC-SIGN and IL10 in the mice were epithelial cells, not immune cells, indicating that the quest to discover SAP’s mechanism of action does not end here.

Although the role of the immune system in mediating the anti-inflammatory and antifibrotic effects of SAP remains unclear, this study exemplified the steps to take in developing new compounds to treat specific diseases.

N. Cox et al., DC-SIGN activation mediates the differential effects of SAP and CRP on the innate immune system and inhibits fibrosis in mice. Proc. Nat. Acad. Sci. U.S.A. 10.1073/pnas.1500956112 (2015). [Abstract]

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