IL-27R–Mediated Regulation of IL-17 Controls the Development of Respiratory Syncytial Virus–Associated Pathogenesis

• Published in: The American journal of pathology Vol. 184; no. 6; pp. 1807 - 1818
• Main Authors: de Almeida Nagata, Denise E, Demoor, Tine, Ptaschinski, Catherine, Ting, Hung-An, Jang, Sihyug, Reed, Michelle, Mukherjee, Sumanta, Lukacs, Nicholas W
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-06-2014; American Society for Investigative Pathology
• Subjects: Animals; Chloride Channels - genetics; Chloride Channels - immunology; Interleukin-17 - genetics; Interleukin-17 - immunology; Interleukins - genetics; Interleukins - immunology; Mice; Mice, Knockout; Minor Histocompatibility Antigens; Mucin 5AC - genetics; Mucin 5AC - immunology; Mucoproteins - genetics; Mucoproteins - immunology; Mucus - immunology; Pathology; Receptors, Cytokine - genetics; Receptors, Cytokine - immunology; Regular; Respiratory Syncytial Virus Infections - genetics; Respiratory Syncytial Virus Infections - immunology; Respiratory Syncytial Virus Infections - pathology; Respiratory Syncytial Viruses - immunology; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - immunology; Th17 Cells - immunology; Th17 Cells - pathology; Th2 Cells - immunology; Th2 Cells - pathology
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2014.02.004

IL-27 is a heterodimeric cytokine composed of the subunits p28 and Epstein-Barr virus induced gene (EBI)-3 and is known for its effects on T-cell function and differentiation. IL-27 signals through the widely expressed IL-27 receptor (IL-27R), composed of the ligand-specific IL-27Rα chain and gp130. Engagement of the IL-27R activates STAT1 signaling, induces the expression of the type 1 helper T-cell (Th1) cytokine, interferon γ, and suppresses the differentiation of Th2 and Th17 cells. This study investigates the role of IL-27 signaling in respiratory syncytial virus (RSV) infection using IL-27Rα–deficient mice (IL-27rKO). Analysis of lungs from RSV-infected IL-27rKO mice showed exacerbation of mucus secretion compared with wild type, as well as enhanced expression of Muc5ac and Gob5 mRNA, markers of goblet cell metaplasia/hyperplasia. When compared with wild-type mice, RSV-challenged IL-27rKO mice had enhanced expression of Th17-associated cytokine IL-17a and an imbalance between Th1 and Th2 cytokine levels. Neutralization of IL-17 in RSV-infected IL-27rKO mice resulted in a significant decrease in the pulmonary mucus response and inhibition of the Th2-associated cytokines. Interestingly, IL-17 blockage led to an increase in the expression of IL-27 subunits p28 and EBI-3 in the lungs and lymph nodes of RSV-infected mice. Thus, IL-27 functions as a regulatory cytokine during RSV pathogenesis by suppressing the development of Th17 cells, but it also appears to be regulated by IL-17 induced by the virus.