Identification of UVB-induced TREM-1 positive tolerogenic DCs and TREM-1 signaling as a target in the prevention of UVB-induced immune suppression and skin carcinogenesis

Ultraviolet radiation B (UVB)-induced dysfunction of dendritic cells (DCs) is a key mechanism for UVB-induced immune suppression, a major risk factor for skin cancer development. Mechanisms remain to be fully understood despite numerous efforts. The current study found that the signaling pathway of triggering receptor expressed on myeloid cells 1 (TREM-1) was a top-upregulated canonical pathway in mouse and human skin after UVB. Blocking TREM-1 with an antagonistic peptide LP-17 significantly reversed UVB-induced suppression of immune responses, suppressed UVB-induced skin carcinogenesis, and prevented the UVB-induced suppression of antigen-specific CD8+ Tc1 and Tc17 effector cells. Further studies defined a TREM-1+ tolerogenic DC subset in the draining lymph nodes, which was induced by UVB. The conditional knockout of the Trem1 gene in CD11c+ DCs abolished UVB-induced suppression of contact hypersensitivity responses. In contrast, it did not affect the immune response in mice that were not exposed to UVB. Mechanistically, blocking TREM-1 significantly increased the expression level of the activation markers CD80 and CD86 by UVB-induced TREM-1+ DCs. In conclusion, our studies have identified a UVB-induced TREM-1+ tolerogenic DC subset and demonstrated an important mechanism for UVB-induced immune suppression and skin carcinogenesis.