AbstractTNF-α is a cytokine associated with inflammatory diseases, including asthma. Increased levels of TNF-α were found in the bronchoalveolar lavage fluid of mice undergoing a dinitrofluorobenzene (DNFB)-induced non-IgE-mediated pulmonary hypersensitivity reaction. We report in this work that TNF-α increases the susceptibility of sensory neurons to dinitrobenzene sulfonic acid (DNS) and capsaicin, leading to a tracheal vascular hyperpermeability response in DNFB-sensitized and DNS-challenged mice. mAb against TNF-α or the TNFR1 inhibited this hyperpermeability response in DNFB-sensitized and DNS-challenged mice. Furthermore, the hyperpermeability response after DNS challenge was abolished in DNFB-sensitized mast cell-deficient WBB6F1-W/WV mice. These animals showed a remarked decrease of TNF-α bronchoalveolar lavage fluid levels after a single DNS challenge. The hyperpermeability response after DNS challenge was regained in mast cell-deficient mice after mast cell reconstitution. These findings indicate a prominent role for TNF-α and its TNFR1 in the DNFB-induced tracheal hyperpermeability response. We propose that a priming effect of mast cell-derived TNF-α on the sensory neurons could be the mechanism of action of TNF-α in the vascular hyperpermeability response in tracheas of mice undergoing a pulmonary hypersensitivity reaction.