Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease

Abstract

Background We have previously shown that Oncostatin M (OSM) is elevated in nasal polyps of chronic rhinosinusitis (CRS) patients, as well as in bronchoalveolar lavage (BAL) fluids after segmental allergen challenge in allergic asthmatics. We also showed in vitro that physiological levels of OSM impair barrier function in differentiated airway epithelium. Objective We sought to determine which hematopoietic or resident cell type(s) were the source of the OSM expressed in mucosal airways disease. Methods Paraffin-embedded NP sections were stained with fluorescence-labeled specific antibodies against OSM, GM-CSF and hematopoietic cell specific markers. Live cells were isolated from NP and matched blood samples for flow cytometric analysis. Neutrophils were isolated from whole blood, cultured with the known OSM inducers GM-CSF and FSTL1, and levels of OSM were measured in the supernatants. Bronchial biopsy sections from controls, moderate asthmatics and severe asthmatics were stained for OSM and neutrophil elastase. Results OSM staining was observed in NP, showed co-localization with neutrophil elastase (n=10), and did not co-localize with markers for eosinophils, macrophages, T cells or B cells (n=3–5). Flow cytometric analysis of NP (n=9) showed that 5.1±2% of CD45+ cells were OSM+, and of the OSM+ cells, 56±7% were CD16+Siglec8−, indicating neutrophil lineage. Only.6±.4% of CD45+ events from matched blood samples (n=5) were OSM+, suggesting that elevated OSM in CRS was locally stimulated and produced. A majority of OSM+ neutrophils expressed Arginase 1 (72.5±12%), suggesting a N2 phenotype. GM-CSF was elevated in nasal polyp tissue compared to control, and was sufficient to induce OSM production (p<.001) in peripheral blood neutrophils in vitro. OSM+ neutrophils were also observed at elevated levels in biopsies from patients with severe asthma. Additionally, OSM protein was elevated in induced sputum from asthmatic patients compared to controls (p<.05). Conclusions Neutrophils are a major source of OSM producing cells in CRS and severe asthma.

Pathophysiologic mechanisms of chronic rhinosinusitis and their roles in emerging disease endotypes

“…35,37,53 A study on patients in Chicago discovered that nasal polyps, which are highly eosinophilic, also have significant levels of neutrophils. 61 Interestingly when comparing subjects with IL-17 + and those with IL-17 − inflammation, or comparing IFN-γ + with IFN-γ − subjects in Caucasians, the IL-17 + and IFN-γ + groups consistently had significantly higher levels of MPO and IL-1β, indicating a contribution of types 1 and 3 immune responses to the development of neutrophilic inflammation. 26 The recently published study by Wang et al demonstrated that increased production and activation of epithelial cell-derived IL-36γ may act on neutrophils and further amplify neutrophilic inflammation in CRS (Fig 2).…”

“…64 Neutrophils have been suggested to impair epithelial barrier function as well, potentially through releasing oncostatin M, an epithelial barrier disrupting cytokine. 61 IFN-γ was reported to induce activated but insufficient autophagy, leading to p62-dependent apoptosis of nasal epithelial cells in CRSwNP. 65 In addition, impaired autophagy in myeloid cells was reported to aggravate eosinophilia, epithelial hyperplasia, and mucosal thickening in mice with eosinophilic CRS.…”

Neutrophilic Inflammation in Asthma and Association with Disease Severity

“…One study showed neutrophils to be a major source of the cytokine Oncostatin M, which affected epithelial barrier function in the airways of patients with severe asthma or in those with chronic rhinosinusitis [98]. …”

The oncostatin M‐stromal cell axis in health and disease

“…OSM-producing haematopoietic cells include T cells, monocytes, macrophages, dendritic cells, neutrophils, eosinophils and mast cells. 11,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61] Although the mechanisms that regulate OSM expression are not extensively characterized, several investigators have reported STAT5-dependent induction of OSM expression, particularly when acting downstream of leukemogenic mutations, including the FIP1L1-PDGFRA fusion protein and hyperactive mutant forms of JAK2, KIT and FLT3. [62][63][64][65] Similarly, OSM expression can be induced in a STAT5-dependent fashion by other cytokines, including erythropoietin (Epo), G-CSF (granulocyte colony-stimulating factor), IL-2 and IL-3.…”