THE ROLE OF MAST-CELLS IN THE DEVELOPMENT OF SKIN FIBROSIS IN TIGHT-SKIN MUTANT MICE

Chronic inflammatory conditions can evolve a fibrotic phenotype often associated with an increase in the number of mast cells (MC) near or w ithin the granulation tissue. Despite the potential of MC to mediate f ibrosis, it is unclear whether these cells play a central role in the pathogenesis of fibrosis or whether their presence is simply circumsta ntial. The tight-skin (Tsk) mouse develops an inherited fibrotic disea se (sharing many similarities with the human disease scleroderma, syst emic sclerosis) in which the lesions are associated with increased num bers and heightened granule release implicating MC in the pathogenesis of fibrosis. Despite their close association with the skin fibrosis o f Tsk mice, the precise role of the MC are key elements in the pathoge nesis of Tsk fibrosis, we generated MC deficient mice carrying the Tsk locus by utilizing selective interbreeding between Tsk and mutant mic e deficient in mast cells (W, dominant white-spotting). We found that in the absence of MC, the early natural history of Tsk fibrosis was no t altered. Furthermore, in older (5-7 months) Tsk mice, we found that the number of cutaneous MC was correlated with a more pronounced fibro sis. Therefore, we conclude that Tsk skin lesions are a pleiotropic ma nifestation of the Tsk gene in which MC are involved/recruited by an u ncharacterized mechanism and that subsequent proliferation and activat ion of MC leads to augmentation of fibrosis.