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TLR-3 triggered aggravation of experimental asthma depends on IL-17
Lunding L 1 , Webering S 1 , Vock C 1 , Hölscher C 2 , Fehrenbach H 1 , Wegmann M 1
1
Division of Experimental Pneumology, Research Center Borstel, Airway Research Center North,
Member of the German Center for Lung Research
2
Division of Infection Immunology, Research Center Borstel
Exacerbations represent a distinct characteristic of asthma that imposes considerable morbidity on
patients. Studies that aimed at characterizing the inflammatory pattern of acute asthma exacerbations
displayed a heterogeneous inflammatory infiltrate with eosinophils as well as large numbers of
neutrophils in sputum and broncho-alveolar lavage (BAL), which is different from chronic disease.
Epidemiological surveys suggested viral infections of the respiratory tract as the main trigger.
Respiratory viruses produce double stranded RNA as an intermediate during replication. This can be
sensed by the immune system via toll-like receptor 3 (TLR-3), which could therefore play a critical role
in the pathogenesis of acute asthma exacerbation. Thus, it was the aim to establish a new
exacerbation model of acute asthma and to elucidate the mechanisms underlying TLR-3 triggered
asthma exacerbation. We hypothesized that an exacerbation of the asthmatic phenotype can be
evoked in a mouse model of acute, allergic asthma by intra-nasal application of the synthetic TLR3
ligand poly(I:C).
Mice treated with poly(I:C) showed increased airway hyperresponsivness (AHR) and infiltration of
neutrophils into the lung, i.e. in bronchoalveolar lavage (BAL). The number of eosinophils in BAL as
well as neutrophils was significantly higher in poly(I:C) treated mice compared to asthma control mice.
Increased infiltration of lung tissue with inflammatory cells and increased mucus production was
observed in HE and PAS stained sections. On the mRNA level the expression of pro-inflammatory
cytokines such as IL-5, IL-6, and TNFα and chemokines such as KC, IP-10, and Rantes was
significantly increased. These data were confirmed by increased cytokine levels in the BAL measured
via Cytometric Bead Array (CBA). Although the cytokine IL-17A was not directly measurable in the
BAL, the number of TH17 cells in the lungs were increased in poly(I:C) treated mice. The exacerbation
of experimental asthma induced by poly(I:C) was completely absent in IL-17A deficient mice. In
contrast, deficiency for IL-23, which is essential for the differentiation of TH17 cells, failed to prevent
the asthmatic exacerbation after local application of poly(I:C). These data indicate that IL-17 but not
inevitably TH17 cells contribute to TLR-3 triggered asthma exacerbation in mice.
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