Toluene diisocyanate (TDI) is the most important cause of occupational asthma (OA), and various pathogenic mechanisms have been suggested. Of these mechanisms, neurogenic inflammation is an important inducer of airway inflammation. Transient receptor potential melastatin 8 (TRPM8) is a well-established cold-sensing cation channel that is expressed in both neuronal cells and bronchial epithelial cells. A recent genome-wide association study of TDI-exposed workers found a significant association between the phenotype of TDI-induced OA and the single-nucleotide polymorphism rs10803666, which has been mapped to the TRPM8 gene. We hypothesized that TRPM8 located in airway epithelial cells may be involved in the pathogenic mechanisms of TDI-induced OA and investigated its role. Bronchial epithelial cells were treated with TDI in a dose- and time-dependent manner. The expression levels of TRPM8 mRNA and protein were determined by quantitative real-time polymerase chain reaction and western blotting. TDI-induced morphological changes in the cells were evaluated by immunocytochemistry. Alterations in the transcripts of inflammatory cytokines were examined in accordance with TRPM8 activation by TDI. TRPM8 expression at both the mRNA and protein levels was enhanced by TDI in airway epithelial cells. TRPM8 activation by TDI led to significant increases in the mRNA of interleukin (IL)-4, IL-13, IL-25 and IL-33. The increased expression of the cytokine genes by TDI was partly attenuated after treatment with a TRPM8 antagonist. TDI exposure induces increased expression of TRPM8 mRNA in airway epithelial cells coupled with enhanced expression of inflammatory cytokines, suggesting a novel role of TRPM8 in the pathogenesis of TDI-induced OA.

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RATIONALE: Asthma is a heterogeneous chronic pulmonary inflammatory disease, commonly preceded by atopic dermatitis (AD). We have recently shown that systemic IL-22 is induced by epicutaneous (EC) sensitization in a mouse model of AD. We examined whether this IL-22 response contributes to airway inflammation triggered by antigen inhalation in EC sensitized mice. METHODS: Wild type (WT) and Il22-/mice were subjected to EC sensitization with ovalbumin (OVA) or saline followed by intranasal (i.n.) OVA challenge. WT mice were adoptively transferred with OVA TCR-specific Th22 from WT or Il22-/mice and i.n. challenged with OVA. rIL-22, rIL-17A and rTNFa, alone or in combination were instilled intranasally in WT mice. Airway inflammation, mRNA levels in the lungs and airway hyperresponsiveness (AHR) were examined. RESULTS: EC OVA sensitization promoted IL-22 production in the lungs after i.n. challenge. EC OVA sensitized Il22-/mice exhibited diminished eosinophil and neutrophil airway infiltration and decreased AHR following i.n. OVA challenge. Moreover, Il22-/mice exhibited enhanced IFNg, but normal IL-13 and IL-17 production in the lungs. Adoptive transfer of in vitro polarized WT but not IL-22 deficient TCR-OVA specific Th22 cells, which co-express IL-17A and TNFa, promoted a neutrophil-dominated airway inflammation, increased Cxcl1 and Cxcl3 mRNA and enhanced AHR. Intranasal instillation of IL-22 in combination with TNFa, but not IL-17A, caused neutrophilic airway inflammation with increased Cxcl1 and Cxcl3 mRNA and enhanced AHR. CONCLUSIONS: EC sensitization promotes the generation of antigenspecific Th22 cells, which drive neutrophil-dominated airway inflammation and AHR following antigen inhalation, suggesting that IL-22 plays an important role in the atopic march.

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