title: TLR2 Activation Limits Rhinovirus-Stimulated CXCL-10 by Attenuating IRAK-1-Dependent IL-33 Receptor Signaling in Human Bronchial Epithelial Cells.
abstract: Airway epithelial cells are the major target for rhinovirus (RV) infection and express proinflammatory chemokines and antiviral cytokines that play a role in innate immunity. Previously, we demonstrated that RV interaction with TLR2 causes ILR-associated kinase-1 (IRAK-1) depletion in both airway epithelial cells and macrophages. Further, IRAK-1 degradation caused by TLR2 activation was shown to inhibit ssRNA-induced IFN expression in dendritic cells. Therefore, in this study, we examined the role of TLR2 and IRAK-1 in RV-induced IFN-β, IFN-λ1, and CXCL-10, which require signaling by viral RNA. In airway epithelial cells, blocking TLR2 enhanced RV-induced expression of IFNs and CXCL-10. By contrast, IRAK-1 inhibition abrogated RV-induced expression of CXCL-10, but not IFNs in these cells. Neutralization of IL-33 or its receptor, ST2, which requires IRAK-1 for signaling, inhibited RV-stimulated CXCL-10 expression. In addition, RV induced expression of both ST2 and IL-33 in airway epithelial cells. In macrophages, however, RV-stimulated CXCL-10 expression was primarily dependent on TLR2/IL-1R. Interestingly, in a mouse model of RV infection, blocking ST2 not only attenuated RV-induced CXCL-10, but also lung inflammation. Finally, influenza- and respiratory syncytial virus-induced CXCL-10 was also found to be partially dependent on IL-33/ST2/IRAK-1 signaling in airway epithelial cells. Together, our results indicate that RV stimulates CXCL-10 expression via the IL-33/ST2 signaling axis, and that TLR2 signaling limits RV-induced CXCL-10 via IRAK-1 depletion at least in airway epithelial cells. To our knowledge, this is the first report to demonstrate the role of respiratory virus-induced IL-33 in the induction of CXCL-10 in airway epithelial cells.
authors: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;
authors: Shyamala
authors: S
authors: Ganesan
authors: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;
authors: Duc
authors: 0000-0003-0301-4216
authors: D
authors: Pham
authors: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;
authors: Yaxun
authors: Y
authors: Jing
authors: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;
authors: Mohammad
authors: 0000-0002-9763-6544
authors: M
authors: Farazuddin
authors: Department of Physiology & Pharmacology, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada;
authors: Magdalena H
authors: MH
authors: Hudy
authors: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;
authors: Benjamin
authors: B
authors: Unger
authors: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;
authors: Adam T
authors: AT
authors: Comstock
authors: Department of Physiology & Pharmacology, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada;
authors: David
authors: D
authors: Proud
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109.
authors: Adam S
authors: AS
authors: Lauring
authors: Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109; uma.sajjan@temple.edu.
authors: Uma S
authors: US
authors: Sajjan
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology*; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology* / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D000072179:Interleukin-1 Receptor-Like 1 Protein / Q000276:immunology / Q000378:metabolism*; D000067596:Interleukin-33 / Q000276:immunology; D051379:Mice; D010850:Picornaviridae Infections / Q000276:immunology / Q000821:virology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000821:virology; D012229:Rhinovirus / Q000276:immunology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D018925:Chemokines; D016207:Cytokines; C079241:IL1RL1 protein, human; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D053592:Interleukin-1 Receptor-Associated Kinases