Autophagy deficiency in myeloid cells exacerbates eosinophilic inflammation in chronic rhinosinusitis

Publication date: Available online 7 December 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Go Eun Choi, Seung-Yong Yoon, Ji-Yun Kim, Do-Young Kang, Yong Ju Jang, Hun Sik Kim
BackgroundEosinophilic inflammation is a major pathologic feature of chronic rhinosinusitis and is frequently associated with severe refractory disease. Prostaglandin D2 level is elevated in chronic rhinosinusitis and 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 chronic rhinosinusitis and the prostaglandin pathway.ObjectiveTo investigate whether altered function of autophagy is associated with eosinophilic inflammation and dysregulated production of prostaglandin D2 in chronic rhinosinusitis.MethodsWe used myeloid cell-specific deletion of Atg7, which is vital for autophagy, and investigated the effects of impaired autophagy on eosinophilic inflammation in a murine model of eosinophilic chronic rhinosinusitis. The effect of autophagy on prostaglandin D2 production and gene expression profiles associated with allergy and the prostaglandin pathway were assessed.ResultsWe found that impaired autophagy in myeloid cells aggravated eosinophilia, epithelial hyperplasia, and mucosal thickening in eosinophilic chronic rhinosinusitis mice. This aggravation was associated with gene expression profiles that favor eosinophilic inflammation, Th2 response, mast cell infiltration, and prostaglandin D2 dysregulation. Supporting this, prostaglandin D2 production was also significantly increased by impaired autophagy. Among other myeloid cells, macrophages were associated with autophagy deficiency, leading to elevated IL-1β levels. Macrophage depletion or blockade of IL-1 receptor led to alleviation of eosinophilic inflammation and sinonasal anatomic abnormalities associated with autophagy deficiency.ConclusionOur results suggest that impaired autophagy in myeloid cells, particularly macrophages, has a causal role in eosinophilic inflammation and eosinophilic chronic rhinosinusitis pathogenesis.

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Teaser

Autophagy deficiency in myeloid cells, particularly macrophages, is linked to augmented production of PGD2 and eosinophilic inflammation in a murine model of ECRS. Thus, autophagy dysfunction has a causal role in the development of ECRS.


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