Neutrophil hyperresponsiveness contributes to lung pathology in STAT3V463del mice 4304

Abstract Description Hyper-IgE syndrome, or Job’s syndrome, is a rare primary immunodeficiency caused by autosomal dominant-negative STAT3 mutations (STAT3-HIES). Patients exhibit recurrent pulmonary infections and chronic inflammation, which result in severe complications such as pneumatoceles. To determine whether cell-intrinsic neutrophil dysfunction and immune dysregulation contribute to lung pathology, mice ectopically expressing STAT3V463del, a mutation commonly found in patients, were infected intratracheally with Pseudomonas aeruginosa. Histological analysis revealed significant alveolar damage and increased immune cell infiltration in the lungs of infected STAT3V463del mice compared to control mice. In addition, infected STAT3V463del mice showed increased bacterial burden, elevated levels of pro-inflammatory cytokines and chemokines, enhanced neutrophil infiltration and increased expression of degranulation-associated surface proteins in vivo. Moreover, bone marrow-derived neutrophils (BMDN) from STAT3V463del mice demonstrated heightened degranulation and NETosis upon stimulation with either PMA or f-MLF compared to BMDN from wild-type controls. These results suggest that neutrophil hyperresponsiveness contributes to lung damage and immune dysfunction in STAT3-HIES. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)