The protective role of TLR6 in a mouse model of asthma is mediated by IL-23 and IL-17A


MOREIRA A. P. , CAVASSANI K. A. , Ismailoglu U. B. , HULLINGER R., DUNLEAVY M. P. , Knight D. A. , ...Daha Fazla

JOURNAL OF CLINICAL INVESTIGATION, cilt.121, sa.11, ss.4420-4432, 2011 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 121 Konu: 11
  • Basım Tarihi: 2011
  • Doi Numarası: 10.1172/jci44999
  • Dergi Adı: JOURNAL OF CLINICAL INVESTIGATION
  • Sayfa Sayıları: ss.4420-4432

Özet

TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data indicate that TLR6 activation exerts protective effects in asthma. Here, we explored the mechanism or mechanisms through which TLR6 mediates this effect using mouse models of Aspergillus fumigatus-induced and house dust mite antigen-induced (HDM antigen-induced) chronic asthma. Tlr6(-/-) mice with fungal or HDM antigen-induced asthma exhibited substantially increased airway hyperresponsiveness, inflammation, and remodeling compared with WT asthmatic groups. Surprisingly, whole-lung levels of IL-23 and IL-17 were markedly lower in Tlr6(-/-) versus WT asthmatic mice. DCs generated less IL-23 upon activation with lipopolysaccharide, zymosan, or curdlan. Impaired IL-23 generation in Tlr6(-/-) mice also corresponded with lower levels of expression of the pathogen-recognition receptor dectin-1 and expansion of Th17 cells both in vivo and in vitro. Exogenous IL-23 treatment of asthmatic Tlr6(-/-) mice restored IL-17A production and substantially reduced airway hyperresponsiveness, inflammation, and lung fungal burden compared with that in untreated asthmatic Tlr6(-/-) mice. Together, our data demonstrate that TLR6 activation is critical for IL-23 production and Th17 responses, which both regulate the allergic inflammatory response in chronic fungal-induced asthma. Thus, therapeutics targeting TLR6 activity might prove efficacious in the treatment of clinical asthma.