| First Author | Reed M | Year | 2015 |
| Journal | Mucosal Immunol | Volume | 8 |
| Issue | 5 | Pages | 1118-30 |
| PubMed ID | 25669150 | Mgi Jnum | J:329659 |
| Mgi Id | MGI:6757313 | Doi | 10.1038/mi.2015.3 |
| Citation | Reed M, et al. (2015) Deficiency of autophagy protein Map1-LC3b mediates IL-17-dependent lung pathology during respiratory viral infection via ER stress-associated IL-1. Mucosal Immunol 8(5):1118-30 |
| abstractText | While recent studies suggest that interleukin (IL)-1beta production is modulated by macroautophagy or sensors of endoplasmic reticulum (ER) stress upon pro-inflammatory insult, autophagy and IL-1beta production during viral infection has not been fully investigated. This was addressed using respiratory syncytial virus (RSV), which is associated with lung immunopathology, IL-1, and IL-17a secretion in severely infected patients. Mice deficient in the autophagy-associated protein Map1-LC3b (LC3b(-/-)) developed increased IL-17a-dependent lung pathology upon infection. RSV-infected LC3b(-/-) dendritic cells (DCs) fail to upregulate autophagosome formation, secrete IL-1beta and IL-6, and elicit IL-17a production from CD4+ T cells. Bone marrow chimeras revealed that both structural and hematopoietic LC3b deficiency contribute to the development of IL-17a-dependent lung pathology in vivo. Further investigation revealed airway epithelium as the primary source of IL-1beta during infection, whereas inhibition of the ER-stress sensor inositol-requiring protein-1 in primary airway epithelial cells reduced IL-1beta production identifying a primary ER stress pathway. Finally, blockade of IL-1 receptor signaling in RSV-infected LC3b(-/-) mice abolished IL-17a-dependent lung pathology. These findings provide novel mechanistic insight into the contribution of autophagy- and ER stress-dependent cytokine production that initiate and maintain aberrant Th17 responses, while identifying IL-1 as a potential therapeutic target in the treatment of severe respiratory viral infections. |
