Traber Katrina E, Hilliard Kristie L, Allen Eri, Wasserman Gregory A, Yamamoto Kazuko, Jones Matthew R, Mizgerd Joseph P, Quinton Lee J
1 Pulmonary Center and.
Departments of 2 Medicine.
Am J Respir Cell Mol Biol. 2015 Oct;53(4):479-88. doi: 10.1165/rcmb.2014-0342OC.
Acute bacterial pneumonia is a significant public health concern worldwide. Understanding the signals coordinating lung innate immunity may foster the development of therapeutics that limit tissue damage and promote host defense. We have previously shown that lung messenger RNA expression of the IL-6 family cytokine oncostatin-M (OSM) is significantly elevated in response to bacterial stimuli. However, its physiological significance during pneumonia is unknown. Here we demonstrate that OSM is rapidly increased in the airspaces of mice after pulmonary infection with Escherichia coli. Neutralization of OSM caused a substantial decrease in airspace neutrophils and macrophages. OSM blockade also caused a marked reduction in lung chemokine (C-X-C motif) ligand (CXCL) 5 expression, whereas other closely related neutrophil chemokines, CXCL1 and CXCL2, were unaffected. Intratracheal administration of recombinant OSM was sufficient to recapitulate the effect on CXCL5 induction, associated with robust activation of the signal transducer and activator of transcription 3 (STAT3) transcription factor. Cell sorting revealed that OSM effects were specific to lung epithelial cells, including a positive feedback loop in which OSM may facilitate expression of its own receptor. Finally, in vitro studies demonstrated that STAT3 was required for maximal OSM-induced CXCL5 expression. These studies demonstrate a novel role for OSM during pneumonia as an important signal to epithelial cells for chemokine induction mediating neutrophil recruitment.
急性细菌性肺炎是全球重大的公共卫生问题。了解协调肺部固有免疫的信号可能会促进限制组织损伤并增强宿主防御能力的治疗方法的开发。我们之前已经表明，白细胞介素-6家族细胞因子制瘤素-M（OSM）的肺信使核糖核酸表达在受到细菌刺激后会显著升高。然而，其在肺炎期间的生理意义尚不清楚。在此我们证明，小鼠肺部感染大肠杆菌后，气腔内的OSM会迅速增加。中和OSM会导致气腔中性粒细胞和巨噬细胞大量减少。阻断OSM还会导致肺趋化因子（C-X-C基序）配体（CXCL）5表达显著降低，而其他密切相关的中性粒细胞趋化因子CXCL1和CXCL2则不受影响。气管内给予重组OSM足以重现对CXCL5诱导的作用，这与信号转导和转录激活因子3（STAT3）转录因子的强烈激活有关。细胞分选显示，OSM的作用对肺上皮细胞具有特异性，包括一个正反馈环，其中OSM可能会促进其自身受体的表达。最后，体外研究表明，最大程度的OSM诱导的CXCL5表达需要STAT3。这些研究证明了OSM在肺炎期间作为向上皮细胞发出的诱导趋化因子以介导中性粒细胞募集的重要信号的新作用。
