SPP 1394, Subproject: Mast cell regulated innate immunity in otitis media; pro-inflammatory and immunosuppressive effects of mast cells in otitis media

Otitis media is a major health problem causing substantial morbidity and resulting in substantial health care expenditures. The causes and treatment of this disorder remain incompletely understood. Mast cells are the only resident leukocytes in the normal middle ear. We observed that in the absence of mast cells, the resolution of otitis media is significantly delayed. These data suggest that the mast cell may play an important role in the innate and cognate defense of the middle ear, and may contribute to otitis media pathogenesis. At other sites, mast cells have recently been demonstrated not only to act pro-inflammatory but also immunosuppressive. We propose a series of integrated experiments employing genetically modified mice to validate these hypotheses and to elucidate the mechanism(s) by which mast cells operate in the middle ear. Mast cells deficient in TNF will be used to reconstitute the middle ear mast cell populations of mast cell deficient mice in continuation of our previous studies in TNF deficient mice. The course of bacterial otitis media in these mice will be analyzed. To examine the immunosuppressive function of mast cells, bacterial otitis media will be induced in IL-10 k/o mice. Inflammatory reactions in the middle ear mucosa as well as the expression levels of the pro-inflammatory cytokines IL-1α, IL-6 and TNF will be analyzed. These experiments will be repeated in mast cell deficient mice reconstituted with mast cells derived from IL-10 k/o mice to analyze if the observed effects are mast cell dependent.