Huang Hua-Rong, Cho Soo Jung, Harris Rebecca M, Yang Jianjun, Bermejo Santos, Sharma Lokesh, Dela Cruz Charles S, Xu Jin-Fu, Stout-Delgado Heather W
Department of Medicine, Pulmonary and Critical Care, Weill Cornell Medicine, New York, New York.
Department of Respiratory and Critical Care Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; and.
Am J Respir Cell Mol Biol. 2021 May;64(5):579-591. doi: 10.1165/rcmb.2020-0312OC.
Community-acquired pneumonia is the most common type of pneumonia and remains a leading cause of morbidity and mortality worldwide. Although many different pathogens can contribute to pneumonia, is one of the common bacterial pathogens that underlie community-acquired pneumonia. RIPK3 (receptor-interacting protein kinase 3) is widely recognized as a key modulator of inflammation and cell death. To elucidate a potential role of RIPK3 in pneumonia, we examined plasma from healthy control subjects and patients positive for streptococcal pneumonia. In human studies, RIPK3 protein concentrations were significantly elevated and were identified as a potential plasma marker of pneumococcal pneumonia. To expand these findings, we used an murine model of pneumococcal pneumonia to demonstrate that RIPK3 deficiency leads to reduced bacterial clearance, severe pathological damage, and high mortality. Our results illustrated that RIPK3 forms a complex with RIPK1, MLKL (mixed-lineage kinase domain-like protein), and MCU (mitochondrial calcium uniporter) to induce mitochondrial calcium uptake and mitochondrial reactive oxygen species(mROS) production during infection. In macrophages, RIPK3 initiated necroptosis via the mROS-mediated mitochondrial permeability transition pore opening and NLRP3 inflammasome activation via the mROS-AKT pathway to protect against . In conclusion, our study demonstrated a mechanism by which RIPK3-initiated necroptosis is essential for host defense against .
社区获得性肺炎是最常见的肺炎类型，仍然是全球发病和死亡的主要原因。尽管许多不同的病原体都可导致肺炎，但 是社区获得性肺炎的常见细菌病原体之一。RIPK3（受体相互作用蛋白激酶3）被广泛认为是炎症和细胞死亡的关键调节因子。为了阐明RIPK3在肺炎中的潜在作用，我们检测了健康对照受试者和肺炎链球菌肺炎阳性患者的血浆。在人体研究中，RIPK3蛋白浓度显著升高，并被确定为肺炎球菌肺炎的潜在血浆标志物。为了扩展这些发现，我们使用肺炎球菌肺炎的 小鼠模型来证明RIPK3缺陷导致细菌清除减少、严重的病理损伤和高死亡率。我们的结果表明，在 感染期间，RIPK3与RIPK1、MLKL（混合谱系激酶结构域样蛋白）和MCU（线粒体钙单向转运体）形成复合物，诱导线粒体钙摄取和线粒体活性氧（mROS）产生。在巨噬细胞中，RIPK3通过mROS介导的线粒体通透性转换孔开放启动坏死性凋亡，并通过mROS-AKT途径激活NLRP3炎性小体以抵御 。总之，我们的研究证明了一种机制，即RIPK3启动的坏死性凋亡对于宿主抵御 至关重要。
