Mast cell-derived TNF promotes Th17 cell-dependent neutrophil-dominant airway inflammation

IL-17 can contribute to host defense and autoimmunity, in part by orchestrating neutrophil recruitment. IL-17 also has been implicated in non-atopic asthma, in which the airway inflammation can include many neutrophils. We used ovalbumin-specific TCR-expressing C57BL/6-OTII mice to characterize the roles of mast cells and T cells in a new model of antigen (Ag)- and T cell-dependent airway neutrophilia. We found that Th17 cells and mast cells, but neither Th1 cells, Th2 cells nor antibody/Ag/FcRγ-signaling, contributed significantly to the Ag-dependent airway neutrophilia elicited in this model. Indeed, IFN-γsignificantly suppressed IL-17-dependent airway neutrophilia in this setting. We detected no significant role for the candidate mast cell products histamine, PGD2, LTB4, CXCL10 or IL-16 in the neutrophil infiltration elicited in this model. By contrast, IL-18, IL-1β and TNF each contributed significantly to Th17 differentiation and the development of Ag- and Th17 cell-mediated airway neutrophilia. Moreover, we found that IL-17 enhanced mast cell-TNF production in vitro and that mast cell-associated TNF contributed significantly to Ag- and Th17 cell-mediated airway neutrophilia in vivo. These findings establish that mast cells can significantly enhance, by antibody- and FcRγg–independent mechanisms, an Ag- and Th17 cell-dependent inflammatory response that is characterized by neutrophil recruitment to the affected site.