title: FcγRI mediates serum amyloid P inhibition of fibrocyte differentiation.
abstract: Fibrotic diseases, such as cardiac and pulmonary fibrosis, have a poor prognosis with no FDA approved therapies. Monocyte-derived, fibroblast-like cells, called fibrocytes, participate in the formation of fibrotic lesions. The conserved pentraxin protein SAP inhibits fibrocyte differentiation in cell culture, and injections of SAP significantly reduce fibrosis in several animal models. SAP binds to the receptors for the Fc portion of IgG (FcγR) and has been crystallized bound to FcγRIIa (CD32a). The in vivo activity of SAP appears to be dependent on the FcRγ. We find that mutagenesis of the residues critical for SAP binding to FcγRIIa only moderately decreases the ability of SAP to inhibit fibrocyte differentiation. In murine cells, deletion of FcRγ or FcγRI (CD64) significantly reduced sensitivity to SAP. Deletion of the combination of FcγRIIb, FcγRIIIa, and FcγRIV did not significantly affect sensitivity to SAP, whereas deletion of just the inhibitory receptor FcγRIIb (CD32b) increased sensitivity to SAP. In human cells, siRNA-mediated reduction of FcRγ or FcγRI levels significantly decreased sensitivity to SAP, whereas reduction of FcγRIIb levels increased sensitivity to SAP. These observations suggest that SAP, at least in part, uses FcγRI and FcRγ to inhibit fibrocyte differentiation.
authors.affiliation: Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Crawford
authors.forename: Darrell
authors.initials: D
authors.lastname: Pilling
authors.forename: Richard H
authors.initials: RH
authors.lastname: Gomer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology*; D057809:HEK293 Cells; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000166:cytology*; D034741:RNA, Small Interfering / Q000235:genetics; D017452:Receptors, IgG / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D000683:Serum Amyloid P-Component / Q000494:pharmacology*
chemical_list: C489017:FCGR1A protein, human; C485701:Fcgr1 protein, mouse; D018793:Interleukin-13; D034741:RNA, Small Interfering; D017452:Receptors, IgG; D011994:Recombinant Proteins; D000683:Serum Amyloid P-Component; D016173:Macrophage Colony-Stimulating Factor