Non-canonical Oncostatin M Signaling Provides Protection during Respiratory Viral and Bacterial infections

Pneumonia remains a major global health burden, highlighting the need for host-directed therapies to complement antimicrobial treatment. Here, we identify Oncostatin M (OSM) as a critical regulator of pulmonary host responses during influenza and bacterial pneumonia. Loss of OSM shifted lung macrophages toward a pro-inflammatory phenotype during influenza infection and exacerbated lung injury during bacterial pneumonia, demonstrating an essential role for OSM in limiting immunopathology. Unexpectedly, OSM induced Signal Transducer and Activator of Transcription 3 (STAT3) activation in the absence of the canonical OSM receptor subunit OSMrβ, revealing previously unrecognized non-canonical OSM signaling in the mouse lungs. Consistent with this finding, loss of OSMrβ did not phenocopy the severe disease observed with loss of OSM. Together, these findings identify OSM as a key regulator of pulmonary immunity and reveal unexpected complexity in OSM signaling during pneumonia.