Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis

Background: Eosinophilic inflammation is a major pathologic feature of chronic rhinosinusitis (CRS) and is frequently associated with severe refractory disease. Prostaglandin (PG) D-2 levels are increased in patients with CRS, and PGD(2) is an important contributing factor to eosinophilic inflammation. Autophagy has a pleiotropic effect on immune responses and disease pathogenesis. Recent studies suggest the potential involvement of autophagy in patients with CRS and the PG pathway. Objective: We sought to investigate whether altered function of autophagy is associated with eosinophilic inflammation and dysregulated production of PGD(2) in patients with CRS. Methods: We used myeloid cell-specific deletion of autophagy-related gene 7 (Atg7), which is vital for autophagy, and investigated the effects of impaired autophagy on eosinophilic inflammation in a murine model of eosinophilic chronic rhinosinusitis (ECRS). The effect of autophagy on PGD(2) production and gene expression profiles associated with allergy and the PG pathway were assessed. Results: We found that impaired autophagy in myeloid cells aggravated eosinophilia, epithelial hyperplasia, and mucosal thickening in mice with ECRS. This aggravation was associated with gene expression profiles that favor eosinophilic inflammation, T(H)2 response, mast cell infiltration, and PGD(2) dysregulation. Supporting this, PGD(2) production was also increased significantly by impaired autophagy. Among other myeloid cells, macrophages were associated with autophagy deficiency, leading to increased IL-1 beta levels. Macrophage depletion or blockade of IL-1 receptor led to alleviation of eosinophilic inflammation and sinonasal anatomic abnormalities associated with autophagy deficiency. Conclusion: Our results suggest that impaired autophagy in myeloid cells, particularly macrophages, has a causal role in eosinophilic inflammation and ECRS pathogenesis.