Rhinovirus-induced major airway mucin production involves a novel TLR3-EGFR-dependent pathway.
Mucociliary clearance is a critical innate defense system responsible for clearing up invading pathogens including bacteria and virus. Although the right amount of mucus is good, excessive mucus causes airway obstruction and tends to precipitate disease symptoms. Rhinovirus (RV) is a common cold virus that causes asthma and chronic obstructive pulmonary disease exacerbation. Mucus overproduction has been linked to the pathogenesis of RV-induced diseases and disease exacerbations. However, the molecular mechanism is not clear. In this study, using one of the major airway mucin-MUC5AC as marker, we found that both major and minor groups of RV induced mucin production in primary human epithelial cells and cell line. RV1A (a minor group of RV) could induce mucous cell metaplasia in vivo. Viral replication was needed for RV-induced mucin expression, and this induction was also dependent on TLR3, suggesting the involvement of double-stranded (ds) RNA signaling. Indeed, dsRNA alone could also induce mucin expression. TLR3-mediated mucin induction was negatively regulated by MyD88, and only partially dependent on TRIF, which suggests a departure from well-documented TLR3 signaling paradigm that mediates inflammatory and other innate defense gene inductions. In addition, TLR3 signaling activated epidermal growth factor receptor (EGFR) through inductions of the expression of EGFR ligands (transforming growth factor-alpha and amphiregulin), which in turn activated EGFR-ERK signaling and mucin expression through an autocrine/paracrine loop. This novel coupling of antiviral defense machinery (i.e., TLR3) and major epithelial proliferation/repair pathway (i.e., EGFR) might play an important role in viral-induced airway remodeling and airway disease exacerbation.
Zhu
Lingxiang
L
Division of Translational Biology, the Hamner Institutes for Health Research, Research Triangle Park, North Carolina, USA.
Lee
Pak-Kei
PK
Lee
Wai-Ming
WM
Zhao
Yuhua
Y
Yu
Dongfang
D
Chen
Yin
Y
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D019898:Autocrine Communication; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System; D051379:Mice; D055271:Mucin 5AC / Q000096:biosynthesis*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D019899:Paracrine Communication; D012367:RNA, Viral; D012137:Respiratory System / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000821:virology*; D012229:Rhinovirus / Q000502:physiology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D008024:Ligands; C524678:MUC5AC protein, human; C507779:MYD88 protein, human; D055271:Mucin 5AC; D053594:Myeloid Differentiation Factor 88; D012367:RNA, Viral; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases