Section of Microbiology and Immunology, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Department of Nephrology, Regensburg University Medical Center, Regensburg 93042, Germany.
Sci Adv. 2024 Sep 6;10(36):eadl6162. doi: 10.1126/sciadv.adl6162.
Carbapenem-resistant (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 monocytes and cytokine induction. Depletion of Ly6C monocytes, but not of neutrophils, abrogated lung and extrapulmonary CRKP clearance in ablated mice, suggesting that Ly6C 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 monocytes and their CRKP-killing abilities. Targeting nociceptor signaling could be a therapeutic approach for treating multidrug-resistant Gram-negative infection and pneumonic sepsis.
耐碳青霉烯肠杆菌科（CRKP）可引起肺部革兰氏阴性感染和致命性肺炎性败血症，而目前针对这种疾病的治疗选择有限。肺部被伤害感受器感觉神经元密集支配，这些神经元介导呼吸、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方面的作用尚不清楚。在这里，我们发现，支配肺部的伤害感受器可促进 CRKP 肺炎和肺炎性败血症的发生。在小鼠中敲除伤害感受器可增加肺部 CRKP 的清除率，抑制 CRKP 的跨肺泡传播，并保护小鼠免于体温过低和死亡。此外，敲除伤害感受器可增强中性粒细胞和 Ly6C 单核细胞的募集和细胞因子诱导。在敲除的小鼠中耗尽 Ly6C 单核细胞，但不耗尽中性粒细胞，可消除肺部和肺外 CRKP 的清除，这表明 Ly6C 单核细胞是调节肺炎性败血症的关键细胞群体。此外，神经肽降钙素基因相关肽可抑制 Ly6C 单核细胞中活性氧的诱导及其对 CRKP 的杀伤能力。针对伤害感受器信号的靶向治疗可能是治疗多药耐药性革兰氏阴性感染和肺炎性败血症的一种方法。
