Carbapenem-resistant Klebsiella pneumoniae (CRKP) causes Gram-negative lung infections and fatal pneumonic sepsis for which limited therapeutic options are available. The lungs are densely innervated by nociceptor sensory neurons that mediate breathing, cough, and bronchoconstriction. The role of nociceptors in defense against Gram-negative lung pathogens is unknown. Here, we found that lung-innervating nociceptors promote CRKP pneumonia and pneumonic sepsis. Ablation of nociceptors in mice increased lung CRKP clearance, suppressed trans-alveolar dissemination of CRKP, and protected mice from hypothermia and death. Furthermore, ablation of nociceptors enhanced the recruitment of neutrophils and Ly6C hi monocytes and cytokine induction. Depletion of Ly6C hi monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6C hi monocytes are a critical cellular population to regulate pneumonic sepsis. Further, neuropeptide calcitonin gene–related peptide suppressed the induction of reactive oxygen species in Ly6C hi monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.

中文翻译：

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耐碳青霉烯类肺炎克雷伯菌肺部感染期间，肺神经伤害感受器感觉神经元促进肺炎败血症


耐碳青霉烯类肺炎克雷伯菌 (CRKP) 会导致革兰氏阴性肺部感染和致命性肺炎败血症，而治疗选择有限。肺部受到伤害性感觉神经元的密集支配，介导呼吸、咳嗽和支气管收缩。伤害感受器在防御革兰氏阴性肺部病原体中的作用尚不清楚。在这里，我们发现肺神经伤害感受器促进 CRKP 肺炎和肺炎败血症。消除小鼠伤害感受器可增加肺 CRKP 清除率，抑制 CRKP 跨肺泡传播，并保护小鼠免于体温过低和死亡。此外，伤害感受器的消除增强了中性粒细胞和Ly6C hi 单核细胞的募集以及细胞因子的诱导。 Ly6C hi 单核细胞的耗竭，但中性粒细胞的耗竭，消除了消融小鼠的肺和肺外 CRKP 清除率，表明 Ly6C hi 单核细胞是调节肺炎败血症的关键细胞群。此外，神经肽降钙素基因相关肽抑制了 Ly6C hi 单核细胞中活性氧的诱导及其 CRKP 杀伤能力。靶向伤害感受器信号传导可能是治疗多重耐药革兰氏阴性感染和肺炎败血症的一种治疗方法。