Antimyeloperoxidase antibodies modulate inflammatory responses and activate profibrotic pathways in human monocytes.
Antimyeloperoxidase antibodies modulate inflammatory responses and activate profibrotic pathways in human monocytes.
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DOI：
10.1016/j.jaut.2023.103060
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发表时间：
2023-09
影响因子：
12.8
通讯作者：
Robson, Michael G.
中科院分区：
文献类型：
--
作者：
Florez-Barros, Fernanda;Bearder, Siobhan;Pavlidis, Polychronis;Robson, Michael G.
在抗中性粒细胞胞浆抗体相关性小血管炎(AAV)中发现了抗髓过氧化物酶(抗MPO)和抗蛋白酶3(抗PR3)抗体。我们研究了抗MPO抗体和抗PR3抗体对人单核细胞的影响。外周血单核细胞在包括TLR激动剂、抗MPO抗体和抗PR3抗体的一系列条件下培养，并设置适当的对照组。实验包括完整的转录组图谱和Fc受体的作用评估。当单核细胞被内毒素或R848刺激时，抗MPO抗体而不是抗PR3抗体导致IL-10分泌减少，并对细胞表面标志的表达产生深远的影响。在没有TLR刺激的情况下，抗MPO抗体而不是抗PR3抗体可提高单核细胞存活率。这些作用依赖于Fc受体CD32a。在TLR刺激下，抗MPO而不是抗PR3抗体对6h转录反应的影响是不同的，但我们发现了一组核心转录本可能是重要的。在没有TLR刺激的情况下，24小时时，抗MPO抗体而不是抗PR3抗体对转录反应有很强的影响，并且编码细胞外基质和细胞外基质相关蛋白的基因显著丰富。Ncount的分析证实了许多差异表达的转录本，并支持CD32a的作用。这些数据表明，AAV患者产生的抗MPO而不是抗PR3的抗体对依赖CD32a的单核细胞有广泛的影响。抗MPO抗体而不是抗PR3抗体激活促纤维化转录反应可能有助于了解疾病表型的差异。抗MPO抗体，而不是抗PR3抗体，延长了人单核细胞的存活时间，并深刻改变了对内毒素和R848的反应。这两种作用都需要Fc受体CD32a。单核细胞经抗MPO-Ig G培养后，转录反应指向细胞外基质相关蛋白的表达。这些发现可能与ANCA血管炎的炎症和纤维化有关，并建议进一步研究。
Antimyeloperoxidase (anti-MPO) and antiproteinase 3 (anti-PR3) antibodies are found in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). We investigated the effect of both anti-MPO and anti-PR3 IgG on human monocytes. Peripheral blood monocytes were cultured under a range of conditions that included TLR agonists, anti-MPO IgG and anti-PR3 IgG with appropriate controls. Experiments included whole transcriptome profiling and an assessment of the role of Fc receptors. When monocytes were stimulated with LPS or R848, anti-MPO but not anti-PR3 IgG, caused a reduction in IL-10 secretion and had a profound effect on cell-surface marker expression. Anti-MPO but not anti-PR3 IgG enhanced monocyte survival in the absence of TLR stimulation. These effects depended on the Fc receptor CD32a. With TLR stimulation, the effect of anti-MPO but not anti-PR3 IgG on the transcriptional response at 6 h was variable, but we identified a core set of transcripts likely to be important. Without TLR stimulation, there was a robust effect of anti-MPO but not anti-PR3 IgG on the transcriptional response at 24 h, and there was a highly significant enrichment of genes encoding extracellular matrix and extracellular matrix-associated proteins. Analysis with nCounter confirmed many of the differentially expressed transcripts and supported a role for CD32a. These data show that anti-MPO, but not anti-PR3 IgG, from patients with AAV has wide-ranging effects on monocytes which depend on CD32a. The activation of a profibrotic transcriptional response by anti-MPO but not anti-PR3 IgG may give insights into the differences in disease phenotype. Anti-MPO IgG, but not anti-PR3 IgG, prolonged human monocyte survival and profoundly modified responses to LPS and R848. Both effects required the Fc receptor CD32a. The transcriptional response of monocytes cultured with anti-MPO IgG was directed towards the expression of extracellular matrix associated proteins. These findings may be relevant to inflammation and fibrosis in ANCA vasculitis and suggest transcripts for further study.
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影响因子：
4.6
作者：
O'Brien EC;Abdulahad WH;Rutgers A;Huitema MG;O'Reilly VP;Coughlan AM;Harrington M;Heeringa P;Little MA;Hickey FB
通讯作者：
Hickey FB
影响因子：
1.6
作者：
Comarmond C;Crestani B;Tazi A;Hervier B;Adam-Marchand S;Nunes H;Cohen-Aubart F;Wislez M;Cadranel J;Housset B;Lloret-Linares C;Sève P;Pagnoux C;Abad S;Camuset J;Bienvenu B;Duruisseaux M;Hachulla E;Arlet JB;Hamidou M;Mahr A;Resche-Rigon M;Brun AL;Grenier P;Cacoub P;Saadoun D
通讯作者：
Saadoun D
影响因子：
56.9
作者：
MAGUIRE, J;SANTORO, T;KELLY, K
通讯作者：
KELLY, K
影响因子：
6.9
作者：
Homma, S;Matsushita, H;Nakata, K
通讯作者：
Nakata, K
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。
影响因子：
8
作者：
Popat RJ;Hakki S;Thakker A;Coughlan AM;Watson J;Little MA;Spickett CM;Lavender P;Afzali B;Kemper C;Robson MG
通讯作者：
Robson MG