<b>Plasma polymeric immunoglobulin receptor exacerbates lung injury in </b><b><i>Klebsiella</i></b><b><i> pneumoniae</i></b><b>-induced pneumosepsis</b>

To screen proteins associated with sepsis lethality, we selected 12 pairs of plasma samples from 12 sepsis patients, each pair corresponding to the moderate and moribund phases of the same patient. We detected 15 different polymeric immunoglobulin receptor (pIgR)-unique peptides, all of which are located in the extracellular domain of pIgR through tandem-mass tagged mass spectrometry, suggesting the presence of secreted pIgR in the plasma. Importantly, the quantity of pIgR peptides was 42.8% higher in the moribund than moderate plasma. Further analysis showed that the level of plasma pIgR is a potential prognostic marker of sepsis. Using animal models of <i>Klebsiella pneumoniae</i>-induced pneumosepsis and polymicrobial sepsis, we found that plasma pIgR increases sepsis lethality. The deleterious effect of plasma pIgR is likely mediated by caspase-11-dependent pyroptosis of alveolar type 2 epithelial cells in mice of pneumosepsis. The activation of pyroptosis of type 2 epithelial cells by <i>Klebsiella pneumoniae</i> requires the presence of both pIgR and IgM. These findings demonstrate that plasma pIgR plays a detrimental role in sepsis, an infection-induced organ failure syndrome that claims millions of lives annually worldwide.

为筛选与脓毒症致死性相关的蛋白质，我们收集了12名脓毒症患者的12组血浆样本，每组样本对应同一患者的中度脓毒症期与濒死期。通过串联质量标记质谱技术（tandem-mass tagged mass spectrometry）检测到15种独特的多聚免疫球蛋白受体（polymeric immunoglobulin receptor, pIgR）特异性肽段，所有肽段均定位于pIgR的胞外结构域，提示血浆中存在分泌型pIgR。值得注意的是，濒死期血浆中的pIgR肽段含量较中度脓毒症期升高42.8%。进一步分析表明，血浆pIgR水平可作为脓毒症的潜在预后标志物。利用肺炎克雷伯菌（Klebsiella pneumoniae）诱导的肺脓毒症模型与多重菌血症脓毒症模型，我们发现血浆pIgR会加剧脓毒症致死风险。血浆pIgR的有害效应可能通过半胱天冬酶-11（caspase-11）依赖性焦亡介导，作用于肺脓毒症小鼠的肺泡II型上皮细胞。肺炎克雷伯菌对II型上皮细胞焦亡的激活，同时需要pIgR与免疫球蛋白M（IgM）的共同参与。上述研究结果表明，血浆pIgR在脓毒症中发挥有害作用；脓毒症是一种由感染诱发的器官功能衰竭综合征，每年在全球范围内造成数百万例患者死亡。