| Title | TLR2 Activation Limits Rhinovirus-Stimulated CXCL-10 by Attenuating IRAK-1-Dependent IL-33 Receptor Signaling in Human Bronchial Epithelial Cells. | ||
| Author | Ganesan, Shyamala; Pham, Duc; Jing, Yaxun; Farazuddin, Mohammad; Hudy, Magdalena H; Unger, Benjamin; Comstock, Adam T; Proud, David; Lauring, Adam S; Sajjan, Uma S | ||
| Journal | J Immunol | Publication Year/Month | 2016-Sep |
| PMID | 27503209 | PMCID | PMC5070654 |
| Affiliation + expend | 1.Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;;Department of Physiology & Pharmacology, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada;;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;;Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109;;Department of Physiology & Pharmacology, University of Calgary Faculty of Medicine, Calgary, Alberta T2N 4N1, Canada;;Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; and Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI 48109. | ||
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-beta, IFN-lambda1, 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.