title: Deficiency of autophagy protein Map1-LC3b mediates IL-17-dependent lung pathology during respiratory viral infection via ER stress-associated IL-1.
abstract: While recent studies suggest that interleukin (IL)-1β production is modulated by macroautophagy or sensors of endoplasmic reticulum (ER) stress upon pro-inflammatory insult, autophagy and IL-1β 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-1β 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-1β during infection, whereas inhibition of the ER-stress sensor inositol-requiring protein-1 in primary airway epithelial cells reduced IL-1β 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.
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: M
authors: M
authors: Reed
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: S H
authors: SH
authors: Morris
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: A B
authors: AB
authors: Owczarczyk
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors: N W
authors: NW
authors: Lukacs
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency* / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology
chemical_list: C587672:IL1B protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins