Monomeric C-reactive protein promotes platelets to release mitochondrial DNA in anti-neutrophil cytoplasmic antibody-associated vasculitis
Monomeric C-reactive protein promotes platelets to release mitochondrial DNA in anti-neutrophil cytoplasmic antibody-associated vasculitis
复制标题
单体 C 反应蛋白促进血小板释放抗中性粒细胞胞质抗体相关性血管炎中的线粒体 DNA
DOI：
10.1016/j.molimm.2021.07.007
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发表时间：
2021-07-19
影响因子：
3.6
通讯作者：
Yan, Tie-Kun
中科院分区：
文献类型：
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作者：
Chen, Tong;Xu, Peng-Cheng;Yan, Tie-Kun
尽管高水平的循环C反应蛋白(PCRP)被认为是疾病活动性的生物标志物，但CRP在抗中性粒细胞胞浆抗体(ANCA)相关性小血管炎(AAV)发病机制中的意义尚不清楚。我们曾在AAV中报道，五聚体C反应蛋白(PCRP)可以解离成单体C反应蛋白(MCRP)并激活血小板。最近的研究表明，活化的血小板可以释放线粒体DNA(MtDNA)。本研究的目的是进一步研究AAV患者mCRP与血小板的关系。我们发现AAV患者血浆mCRP水平明显高于正常对照组，且与mCRP阳性血小板比例呈正相关。1例正常供者的血小板可被5例AAV患者的血浆激活，去除mCRP后这种激活作用可被减弱。仅需0.1mU g/mL的重组mCRP即可通过与脂筏相互作用，通过p38MAPK/NF-kappa B途径诱导血小板释放mtDNA。MCRP与血小板的结合依赖于C端八肽(AA 199-206)。释放的mtDNA不能单独诱导呼吸爆发，但在与TLR9结合后可增强ANCA诱导的中性粒细胞呼吸爆发。MCRP激活的血小板释放的mtDNA也促进了血浆凝血酶的生成。综上所述，我们的研究结果表明，mCRP可以通过与脂筏相互作用而与血小板结合，并诱导mtDNA的释放。释放的mtDNA可增强ANCA的致病性，促进AAV凝血系统的激活。
Although high level of circulating C-reactive protein (pCRP) is considered as a biomarker for disease activity, the significance of CRP in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has not been clarified. We once reported in AAV, pentameric CRP (pCRP) could dissociate into monomeric CRP (mCRP) and activate platelets. Recent studies have demonstrated that the activated platelets can release mitochondrial DNA (mtDNA). The purpose of this study was to further study the relationship between mCRP and platelets in AAV. We found the plasma level of mCRP in AAV patients was significantly higher than that of normal control and positively correlated with the proportion of mCRP-positive platelets. Platelets isolated from one normal donor could be activated by plasma from 5 AAV patients and this effect could be attenuated when mCRP had been removed. Only 0.1 mu g/mL of recombinant mCRP was needed for inducing platelets to release mtDNA via interaction with lipid raft and through p38 MAPK/NF-kappa B pathway. The mCRP binding on platelets depended on the C-terminal octapeptide (aa 199-206). The released mtDNA did not induce respiratory burst alone, but enhanced the ANCA-induced neutrophils respiratory burst after binding Toll-like receptor 9 (TLR9). The mtDNA released by mCRP-activated platelets also enhanced thrombin generation of plasma. In conclusion, our data demonstrate that mCRP can bind platelets via interaction with lipid raft and induce the release of mtDNA. The released mtDNA can enhance the pathogenicity of ANCA and promote activation of coagulation system in AAV.