Identifying innate and adaptive immune mechanisms associated with fibrosis in animal models of RDEB
DEBRA
New York Medical College
We recently demonstrated that TGFβ signaling is activated in RDEB (col7a1-/-) mice as early as a week after birth in the interdigital folds of murine paw skin. At the same time, many critical genes involved in wound healing and fibrosis are significantly upregulated. In preliminary studies, we also observed infiltration of significant levels of neutrophils, macrophages, T cells and mast cells in the dermis of newborn and a week-old RDEB mouse skin. This inflammatory response is likely initiated by damage-associated molecular patterns (DAMPs), also known as sterile inflammation, as there is no apparent microbial-associated infection. Sterile inflammation has often shown to result in chronic inflammation and fibrosis. Surprisingly, all these immune cells are later (in two weeks) clustered around hair follicles. Such tropism of T cells to hair follicles resembles the features of skin resident memory T (TRM) cells, which provide rapid immune protection, however, when dysregulated, result in unwanted inflammation and fibrosis. Investigating the early events of sterile inflammation with subsequent microbialassociated infection is critical to understand the mechanisms of chronic inflammation and fibrosis in patients with RDEB. These results will facilitate the development of effective therapeutic strategies to prevent chronic fibrosis in patients with RDEB.
2.1 Biological and endogenous factors