Oncostatin M Limits Lung Injury during Influenza by Modulating Leukocyte Recruitment and Inducing Tissue Repair Factors

Introduction/Rationale: Oncostatin M (OSM), an IL-6 family cytokine, is upregulated during pneumonia. We and others have previously shown that OSM is required for protection during pneumonia. However, the exact mechanisms of how OSM mediates this protection remain a knowledge gap.

Methods: We intratracheally instilled influenza A virus A/HKx31 into the lungs of 6-12-week-old OSM knockout (OSM-/-), OSM receptor knockout (OSMrβ-/-) mice and wild type (WT) controls and measured various outcomes of influenza. To investigate lung cell-type-specific responses to OSM, we performed single-cell RNA sequencing of WT and OSMrβ-/- lungs intratracheally instilled with recombinant mouse OSM or a vehicle control.

Results: During influenza infection, loss of OSM increases morbidity during peak inflammation, leads to greater recruitment of leukocytes including neutrophils, monocytes and lymphocytes, and increases the number of PD-L1 high immunosuppressive alveolar macrophages. Interestingly, we observed no phenotype in OSMrβ-/- compared to WT mice indicating that these effects are OSMrβ independent. Single-cell RNA sequencing and immunofluorescence analyses revealed that OSM activates STAT3 and ERK pathways in lung endothelial cells and fibroblasts and induces the expression of genes that promote tissue repair including proangiogenic factors and Serpins both in the presence and absence of OSMrβ. Since the related IL-6 family receptor, leukemia inhibitory factor receptor (LIFrβ), is highly expressed by these cells, OSM may be signaling through this receptor in OSMrβ-/- cells.

Conclusion: Our study indicates that during influenza, OSM limits excessive leukocyte recruitment and thus helps limit lung injury. OSM signaling in endothelial cells and fibroblasts induces the expression of tissue repair factors that may help regenerate the lungs post influenza infection. Furthermore, OSM may signal through LIFrβ to rescue the loss of OSM-OSMrβ signaling during influenza.