Melanocyte hyaluronan coat fragmentation enhances the UVB-induced TLR-4 receptor signaling and expression of proinflammatory mediators IL-6, IL-8, CXCL-1 and CXCL-10 via NF-κB activation.

Skin is constantly exposed to UV-radiation, the most critical risk factor for melanoma development. Hyaluronan is abundant in the epidermal extracellular matrix and may undergo degradation by UV-radiation. It is hypothesized that an intact hyaluronan coat around the cells protects against various agents including UV-radiation, while hyaluronan fragments promote inflammation and tumorigenesis. We investigated whether hyaluronan contributes to the UVB-induced inflammatory responses in primary melanocytes. A single dose of UVB suppressed hyaluronan secretion and the expression of hyaluronan synthases HAS2, HAS3, the hyaluronan receptor CD44 and the hyaluronidase HYAL2, as well as induced the expression of inflammatory mediators IL-6, IL-8, CXCL-1 and CXCL-10. Silencing HAS2 and CD44 partly inhibited the inflammatory response, suggesting that hyaluronan coat is involved in the process. UVB alone caused little changes in the coat, while its removal with hyaluronidase during the recovery from UVB-exposure dramatically enhanced the surge of these inflammatory mediators via TLR-4, p38 and NF-κB. Interestingly, exogenous hyaluronan fragments did not reproduce the inflammatory effects of hyaluronidase. We hypothesize that the hyaluronan coat on melanocytes is a sensor of tissue injury. Combined with UVB-exposure, repeated injuries to the hyaluronan coat could maintain a sustained inflammatory state associated with melanomagenesis.