Department of Biochemistry and Cell Biology, Rice University, Houston, TX, USA.
J Leukoc Biol. 2012 Oct;92(4):699-711. doi: 10.1189/jlb.0112033. Epub 2012 Apr 9.
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.
纤维化疾病，如心脏和肺纤维化，预后不良，没有获得 FDA 批准的治疗方法。单核细胞衍生的成纤维细胞样细胞，称为纤维细胞，参与纤维化病变的形成。保守的 pentraxin 蛋白 SAP 在细胞培养中抑制成纤维细胞分化，SAP 的注射显著减少几种动物模型中的纤维化。SAP 与 IgG Fc 部分的受体（FcγR）结合，并已与 FcγRIIa（CD32a）结合结晶。SAP 的体内活性似乎依赖于 FcRγ。我们发现，SAP 与 FcγRIIa 结合的关键残基的突变仅适度降低 SAP 抑制成纤维细胞分化的能力。在鼠细胞中，FcRγ 或 FcγRI（CD64）的缺失显著降低了对 SAP 的敏感性。FcγRIIb、FcγRIIIa 和 FcγRIV 的组合缺失对 SAP 的敏感性没有显著影响，而仅仅抑制性受体 FcγRIIb（CD32b）的缺失增加了对 SAP 的敏感性。在人细胞中，FcRγ 或 FcγRI 水平的 siRNA 介导降低显著降低了对 SAP 的敏感性，而 FcγRIIb 水平的降低增加了对 SAP 的敏感性。这些观察结果表明，SAP 至少部分地使用 FcγRI 和 FcRγ 来抑制成纤维细胞分化。
