Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development.
Anti-myeloperoxidase antibodies attenuate the monocyte response to LPS and shape macrophage development.
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抗髓过氧化物酶抗体减弱了对LPS的单核反应并塑造巨噬细胞的发展。
DOI：
10.1172/jci.insight.87379
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发表时间：
2017-01-26
期刊：
影响因子：
8
通讯作者：
Robson MG
中科院分区：
文献类型：
--
作者：
Popat RJ;Hakki S;Thakker A;Coughlan AM;Watson J;Little MA;Spickett CM;Lavender P;Afzali B;Kemper C;Robson MG
抗中性粒细胞胞浆抗体 (ANCA) 血管炎的特征是存在针对髓过氧化物酶和蛋白酶 3 的自身抗体，除了中性粒细胞外，它们还结合单核细胞。虽然 ANCA 对中性粒细胞的病理作用已被承认，但 ANCA 对单核细胞功能的影响尚不清楚。使用患者的 IgG，我们研究了这些自身抗体对单核细胞的影响，发现抗髓过氧化物酶抗体 (MPO-ANCA) 减少了 LPS 响应下的 IL-10 和 IL-6 分泌。 IL-10 和 IL-6 的减少依赖于 Fc 受体和酶促髓过氧化物酶，并伴随着 TLR 驱动的信号通路的显着减少。与 TLR 信号的变化相一致，在 MPO-ANCA 存在的情况下，单核细胞中作为 TLR4 拮抗剂的氧化磷脂增加。我们进一步观察到 MPO-ANCA 通过刺激 CSF-1 的产生来增加单核细胞的存活和分化为巨噬细胞。然而，这与髓过氧化物酶酶活性和 TLR 信号传导无关。在 MPO-ANCA 存在下分化的巨噬细胞分泌更多的 TGF-β，并进一步促进分泌 IL-10 和 TGF-β 的 CD4+ T 细胞的发育。因此，MPO-ANCA 可能通过减少单核细胞分泌抗炎性 IL-10 来促进炎症，并且 MPO-ANCA 可以改变巨噬细胞和 T 细胞的发育，从而可能促进纤维化。抗中性粒细胞胞浆抗体 (ANCA) 血管炎患者的抗髓过氧化物酶抗体除了先前描述的对中性粒细胞的影响外，还会改变单核细胞功能。
Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition to neutrophils. While a pathological effect on neutrophils is acknowledged, the impact of ANCA on monocyte function is less well understood. Using IgG from patients we investigated the effect of these autoantibodies on monocytes and found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 and IL-6 secretion in response to LPS. This reduction in IL-10 and IL-6 depended on Fc receptors and enzymatic myeloperoxidase and was accompanied by a significant reduction in TLR-driven signaling pathways. Aligning with changes in TLR signals, oxidized phospholipids, which function as TLR4 antagonists, were increased in monocytes in the presence of MPO-ANCA. We further observed that MPO-ANCA increased monocyte survival and differentiation to macrophages by stimulating CSF-1 production. However, this was independent of myeloperoxidase enzymatic activity and TLR signaling. Macrophages differentiated in the presence of MPO-ANCA secreted more TGF-β and further promoted the development of IL-10– and TGF-β–secreting CD4+ T cells. Thus, MPO-ANCA may promote inflammation by reducing the secretion of antiinflammatory IL-10 from monocytes, and MPO-ANCA can alter the development of macrophages and T cells to potentially promote fibrosis. Anti-myeloperoxidase antibodies from patients with anti-neutrophil cytoplasmic antibody (ANCA) vasculitis alter monocyte function in addition to previously described effects on neutrophils.