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

Lee, Y.; Patneaude, L. J.; Martins, K. R.; Pihl, R. M. F.; Dimbo, E. L.; Perez-Vazquez, M.; Jayaraman, A.; Crossey, E.; Armstrong, E. M. R.; Hiller, B. E.; Garza, I.; Bosmann, M.; Jones, M. R.; Mizgerd, J. P.; Quinton, L. J.; Traber, K. E.

doi:10.64898/2026.07.30.741615

bioRxiv · 10.64898/2026.07.30.741615

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

Lee, Y.·Patneaude, L. J.·Martins, K. R.·Pihl, R. M. F.·Dimbo, E. L.·Perez-Vazquez, M.·Jayaraman, A.·Crossey, E.·Armstrong, E. M. R.·Hiller, B. E.·Garza, I.·Bosmann, M.·Jones, M. R.·Mizgerd, J. P.·Quinton, L. J.·Traber, K. E.

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Abstract

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 OSMr{beta}, revealing previously unrecognized non-canonical OSM signaling in the mouse lungs. Consistent with this finding, loss of OSMr{beta} 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.

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Lee, Y., Patneaude, L. J., Martins, K. R., Pihl, R. M. F., Dimbo, E. L., Perez-Vazquez, M., Jayaraman, A., Crossey, E., Armstrong, E. M. R., Hiller, B. E., Garza, I., Bosmann, M., Jones, M. R., Mizgerd, J. P., Quinton, L. J., Traber, K. E.. 2026-08-04. Non-canonical Oncostatin M Signaling Provides Protection during Respiratory Viral and Bacterial infections. https://doi.org/10.64898/2026.07.30.741615

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