Induction of STAT3-Dependent CXCL5 Expression and Neutrophil Recruitment by Oncostatin-M during Pneumonia

Abstract

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.

Pneumonia recovery reprograms the alveolar macrophage pool

“…Among soluble immune mediators altered by prior experience in the macrophage transcriptomes ( Figure 9, A and B), Cxcl9 was of interest for being the only chemokine increased by experience and Osm for encoding oncostatin M, which enhances lung neutrophil recruitment by stimulating CXCL5 expression in epithelial cells (39,43). Both of these cytokines were measured by ELISA in lung homogenates at early time points of pneumonia in naive and experienced mice, and both were increased at the protein level by 7 hours of infection ( Figure 9F).…”

IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K. pneumoniae

“…Another study using an E. coli pneumonia model demonstrated that a bacterial clearance defect when ablating Onconstatin-M during pneumonia was also dependent on the epithelial expression of Cxcl5 (Traber et al, 2015). These studies together with the present study emphasize the important role of epithelial derived CXCL5-secreting cells in orchestrating PMN recruitment to bacterial infection in the lung.…”

NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis

“…Immunoblotting. Whole-liver-tissue protein was extracted as described previously (58). Briefly, liver tissues were isolated and homogenized in extraction buffer with 2.0-mm zirconium oxide beads (catalog number ZROB20; Next Advance) using a Bullet Blender tissue homogenizer.…”