Myeloid expression of the anti-apoptotic protein Mcl1 is required in anti-myeloperoxidase vasculitis but myeloperoxidase inhibition is not protective.
Myeloid expression of the anti-apoptotic protein Mcl1 is required in anti-myeloperoxidase vasculitis but myeloperoxidase inhibition is not protective.
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DOI：
10.1016/j.kint.2022.08.028
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发表时间：
2023-01
影响因子：
19.6
通讯作者：
Robson, Michael G.
中科院分区：
文献类型：
--
作者：
Florez-Barros, Fernanda;Bearder, Siobhan;Kull, Bengt;Freeman, Adrian;Mocsai, Attila;Robson, Michael G.
抗中性粒细胞和单核细胞髓过氧化物酶和蛋白酶 3 的抗体是抗中性粒细胞胞浆抗体血管炎的一个特征，这种疾病发病率很高，需要新的治疗方法。骨髓特异性删除抗凋亡蛋白 Mcl1 的小鼠，循环中性粒细胞的数量减少。在此，我们评估了小鼠抗髓过氧化物酶血管炎是否需要骨髓特异性 Mcl1，以及髓过氧化物酶的抑制是否具有保护作用。在抗髓过氧化物酶抗体诱导的抗中性粒细胞胞浆抗体血管炎小鼠模型中，具有骨髓特异性 Mcl1 缺失的小鼠免受疾病侵害。与对照组相比，他们的肾小球中的新月体、中性粒细胞和巨噬细胞较少，血清肌酐水平较低，蛋白尿也较少。在基线和疾病诱导后第六天，他们的循环中性粒细胞比对照组少。第六天，循环单核细胞也减少了。 AZD5904 抑制髓过氧化物酶对疾病的组织学或生化参数没有影响，并且在疾病诱导后第一天、第二天、第五天或第七天白蛋白尿也没有减少。当在没有粒细胞集落刺激因子的情况下诱导疾病时，这些发现仍然存在，这会增加疾病的严重程度。第二种髓过氧化物酶抑制剂 AZM198 也没有显示出任何效果的证据，尽管 AZD5904 和 AZM198 都能在体外抑制人中性粒细胞胞外陷阱的形成。因此，我们的结果表明，虽然在这种抗髓过氧化物酶血管炎模型中需要骨髓特异性 Mcl1，但髓过氧化物酶抑制并不具有保护作用。
Antibodies to neutrophil and monocyte myeloperoxidase and proteinase 3 are a feature of anti-neutrophil cytoplasmic antibody vasculitis, a disease with significant morbidity for which new treatments are needed. Mice with a myeloid-specific deletion of the anti-apoptotic protein Mcl1 have reduced numbers of circulating neutrophils. Here, we assessed if myeloid-specific Mcl1 was required in murine anti-myeloperoxidase vasculitis and whether inhibition of myeloperoxidase was protective. In a murine model of anti-neutrophil cytoplasmic antibody vasculitis, induced by anti-myeloperoxidase antibody, mice with a myeloid-specific deletion of Mcl1 were protected from disease. They had fewer crescents, neutrophils, and macrophages in the glomeruli, lower serum creatinine levels and reduced albuminuria compared with controls. At baseline and day six after disease induction they had fewer circulating neutrophils than controls. At day six there were also fewer circulating monocytes. Myeloperoxidase inhibition with AZD5904 had no effect on histological or biochemical parameters of disease, and there was also no reduction in albuminuria at day one, two, five or seven after disease induction. These findings persisted when disease was induced without granulocyte-colony stimulating factor, which increases disease severity. A second myeloperoxidase inhibitor, AZM198, also showed no evidence of an effect, although both AZD5904 and AZM198 inhibited human neutrophil extracellular trap formation in vitro. Thus, our results show that while myeloid-specific Mcl1 is required in this model of anti-myeloperoxidase vasculitis, myeloperoxidase inhibition is not protective.
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DOI：
10.1073/pnas.1708247114
发表时间：
2017-11-07
影响因子：
11.1
作者：
Schreiber, Adrian;Rousselle, Anthony;Kettritz, Ralph
通讯作者：
Kettritz, Ralph
影响因子：
13.6
作者：
Schreiber, Adrian;Pham, Christine T. N.;Kettritz, Ralph
通讯作者：
Kettritz, Ralph
影响因子：
2.2
作者：
Abram CL;Roberge GL;Hu Y;Lowell CA
通讯作者：
Lowell CA
影响因子：
13.3
作者：
Futosi, Krisztina;Kasa, Orsolya;Mocsai, Attila
通讯作者：
Mocsai, Attila
影响因子：
27.4
作者：
Freeley, Simon J.;Coughlan, Alice M.;Robson, Michael G.
通讯作者：
Robson, Michael G.