Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor.
Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor.
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DOI：
10.1002/art.30081
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发表时间：
2011-01
影响因子：
--
通讯作者：
Robinson, William H.
中科院分区：
文献类型：
--
作者：
Sokolove, Jeremy;Zhao, Xiaoyan;Chandra, Piyanka E.;Robinson, William H.
RA与抗瓜氨酸蛋白抗体(ACPA)的存在有关。近三分之二的ACPA阳性RA患者具有含有瓜氨酸纤维蛋白原(CFB)的免疫复合体(IC)，这些含有CFB的IC(CFB-IC)可以加重RA小鼠模型的疾病；然而，这种IC在RA发病机制中的确切作用仍不清楚。在这里，我们研究了一种新的机制，通过该机制，ACPA特异性地针对瓜氨酸纤维蛋白原可以直接刺激巨噬细胞产生肿瘤坏死因子。用天然纤维蛋白原(NFB)、瓜氨酸纤维蛋白原(CFB)或体外产生的NFB-IC或CFB-IC刺激小鼠或人巨噬细胞，用ELISA法测定肿瘤坏死因子的产生。IC由多克隆抗FB抗体或来自ACPA阳性RA患者的混合免疫球蛋白生成。为探讨Toll样受体4(Toll-like Receptor 4，TLR4)-MyD88通路和Fcγ受体(FcγR，FcγR)通路在FB和FB IC诱导巨噬细胞产生肿瘤坏死因子中的作用，用(I)Toll样受体4(TLR4)或MYD88缺乏的巨噬细胞，以及(Ii)TLR4或Fc NFB R的抑制剂，CFB比NFB更有效地刺激巨噬细胞产生肿瘤坏死因子。在IC中加入CFB可增强其刺激巨噬细胞产生肿瘤坏死因子的能力。CFB-IC对肿瘤坏死因子的刺激依赖于TLR4和MYD88，而CFB-IC的刺激依赖于TLR4-MYD88和FcγR。我们的发现表明，瓜氨酸在增加内源性天然免疫配体的效力方面具有潜在的作用，并为抗瓜氨酸自身免疫可能有助于RA炎症的发生和传播的机制提供了洞察。
RA is associated with the presence of anti-citrullinated protein antibodies (ACPA). Nearly two thirds of patients with ACPA-positive RA have immune complexes (IC) that contain citrullinated fibrinogen (cFb), and these cFb-containing IC (cFb-IC) can exacerbate disease in murine models of RA; however, the exact role of such ACPA IC in RA pathogenesis has remained elusive. Here, we investigate a novel mechanism by which ACPA specifically targeting citrullinated fibrinogen may directly stimulate macrophage TNF production. Murine or human macrophages were stimulated with native fibrinogen (nFb), citrullinated fibrinogen (cFb) or in vitro-generated nFb-IC or cFb-IC, and TNF production was measured by ELISA. IC were generated with either polyclonal anti-Fb antibodies or pooled IgG from patients with ACPA-positive RA. To evaluate the role of the toll-like receptor 4 (TLR4)-MyD88 pathway and the Fcγ receptor (FcγR) pathway in the induction of TNF by Fb and Fb-IC, parallel experiments were performed using (i) TLR4-deficient or MyD88-deficient macrophages, and (ii) inhibitors of TLR4 or FcγR. cFb stimulated macrophage TNF production more potently than nFb. Incorporation of cFb into IC augmented its ability to stimulate macrophage TNF production. cFb stimulation of TNF was dependent on TLR4 and MyD88, while cFb-IC stimulation was dependent on both TLR4-MyD88 and FcγR. We demonstrate that cFb-IC can co-stimulate macrophages via dual engagement of TLR4 and FcγR, resulting in the synergistic induction of TNF production. Our findings suggest a potential role for citrullination in increasing the potency of an endogenous innate immune ligand and provide insight into the mechanism by which anti-citrulline autoimmunity may contribute to the onset and propagation of inflammation in RA.
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DOI：
10.1179/096805100101532315
发表时间：
2000-01-01
期刊：
JOURNAL OF ENDOTOXIN RESEARCH
影响因子：
--
作者：
Akira, S;Hoshino, K;Kaisho, T
通讯作者：
Kaisho, T
影响因子：
15.9
作者：
Flick, Matthew J.;LaJeunesse, Christine M.;Degen, Jay L.
通讯作者：
Degen, Jay L.
影响因子：
4.4
作者：
Ohashi, K;Burkart, V;Kolb, H
通讯作者：
Kolb, H
影响因子：
4.8
作者：
Asea, A;Rehli, M;Calderwood, SK
通讯作者：
Calderwood, SK
影响因子：
--
作者：
Hueber, W;Kidd, BA;Robinson, WH
通讯作者：
Robinson, WH