LAUSR

Description Bacterial-associated LPS drives oncostatin M–dependent airway inflammation and mucus hypersecretion in severe asthma. Addressing asthma Severe asthma is thought to be driven by bacterial dysbiosis, but the mechanism linking the two remains unclear. Headland et al. sought to understand this mechanism, identifying oncostatin M as a mediator of severe asthma. Blocking oncostatin M with an antibody reduced severe asthma-related symptoms in mice after exposure to bacterial stimuli. Together, these findings support further development of antibodies and other drugs targeting oncostatin M as a treatment for severe asthma. Exacerbations of symptoms represent an unmet need for people with asthma. Bacterial dysbiosis and opportunistic bacterial infections have been observed in, and may contribute to, more severe asthma. However, the molecular mechanisms driving these exacerbations remain unclear. We show here that bacterial lipopolysaccharide (LPS) induces oncostatin M (OSM) and that airway biopsies from patients with severe asthma present with an OSM-driven transcriptional profile. This profile correlates with activation of inflammatory and mucus-producing pathways. Using primary human lung tissue or human epithelial and mesenchymal cells, we demonstrate that OSM is necessary and sufficient to drive pathophysiological features observed in severe asthma after exposure to LPS or Klebsiella pneumoniae. These findings were further supported through blockade of OSM with an OSM-specific antibody. Single-cell RNA sequencing from human lung biopsies identified macrophages as a source of OSM. Additional studies using Osm-deficient murine macrophages demonstrated that macrophage-derived OSM translates LPS signals into asthma-associated pathologies. Together, these data provide rationale for inhibiting OSM to prevent bacterial-associated progression and exacerbation of severe asthma.