Respiratory virus-induced TLR7 activation controls IL-17-associated increased mucus via IL-23 regulation.
The response to respiratory syncytial virus (RSV), negative strand ssRNA virus, depends upon the ability to recognize specific pathogen-associated targets. In the current study, the role of TLR7 that recognizes ssRNA was examined. Using TLR7(-/-) mice, we found that the response to RSV infection in the lung was more pathogenic as assessed by significant increases in inflammation and mucus production. Although there appeared to be no effect of TLR7 deficiency on type I IFN, the pathology was associated with an alteration in T cell responses with increases in mucogenic cytokines IL-4, IL-13, and IL-17. Examination of dendritic cells from TLR7(-/-) animals indicated a preferential activation of IL-23 (a Th17-promoting cytokine) and a decrease in IL-12 production. Neutralization of IL-17 in the TLR7(-/-) mice resulted in a significant decrease in the mucogenic response in the lungs of the RSV-infected mice. Thus, without TLR7-mediated responses, an altered immune environment ensued with a significant effect on airway epithelial cell remodeling and goblet cell hyper/metaplasia, leading to increased mucus production.
Lukacs
Nicholas W
NW
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. nlukacs@umich.edu
Smit
Joost J
JJ
Mukherjee
Sumanta
S
Morris
Susan B
SB
Nunez
Gabriel
G
Lindell
Dennis M
DM
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D020397:Goblet Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006965:Hyperplasia; D020381:Interleukin-17 / Q000276:immunology* / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology* / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009093:Mucus / Q000378:metabolism*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D020381:Interleukin-17; D053759:Interleukin-23; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7