The role of MyD88-dependent signaling pathways in skin mast cells in UVB-induced skin diseases

Abstract

Excessive UV irradiation is a major risk factor for health. While chronic long-term UV exposure induces skin aging and suppression of the immune system, acute UV exposure leads to skin inflammation, also known as sunburn. In the long-term however, both forms of exposure can be detrimental and contribute to the development of skin cancer. UV-induced danger-associated molecular patterns (DAMPs) are thereby generated and mediate inflammation by signaling through toll-like receptors (TLRs) and IL-1 receptor family proteins, among which most receptors use MyD88 as an adaptor protein to transduce intracellular signaling. In chronic UVB irradiation, an important role for mast cell-specific MyD88 signaling was described which affected UV-induced mast cell accumulation. <br /> In this thesis, it was shown that MyD88 is important for the activation and survival of in vitro generated mast cells and that especially IL-33 treatment of mast cells enhances these functions. In vivo blocking of the IL-33 receptor ST2 in chronic UVB irradiation of mice however did not change mast cell accumulation, but affected local skin immune cells, as well as keratinocytes and their proliferative potential, thus regulating acanthosis. Since IL-33 was not the cause for mast cell accumulation, next, the interaction between mast cells and DCs was studied because UV-induced indirect effects might also influence mast cell accumulation. It could be shown that in the skin, these two cell types are located in close proximity to each other and that DCs transfer MHCII molecules to mast cells. Moreover, MyD88 expression in mast cells elevated DC activation in mast cell-DC co-cultures, revealing that MyD88 in mast cells can regulate DC functions and potentially modulate T-cell responses. UVB exposure induced the expansion of Tregs, which are crucial in mediating immunosuppression. In the model of UV-induced immune suppression, UVB irradiation was able to reduce skin inflammation independent of MyD88. Interestingly, MyD88 deficiency led to increased inflammation due to a higher density of neutrophils, monocytes and moDCs in the skin. After long-term UVB irradiation, MyD88 KO mice showed accelerated tumor development compared to MyD88 proficient mice, which was partially rescued by mast cell-specific MyD88 expression. <br /> Overall, in this thesis, the importance of MyD88 for appropriate mast cell functions was highlighted and was shown to alter the immune responses in UV-induced diseases.