Mechanisms of ultraviolet radiation induced immune suppression

University Of Alabama At Birmingham, Birmingham AL

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Abstract

? DESCRIPTION (provided by applicant): Ultraviolet radiation (UVR) is a major environmental hazard which has variety of adverse biological effects. It causes immune suppression which is a major risk factor for skin cancer. Perturbations of UVR induced immune suppression have also been implicated in photodermatological diseases such as polymorphous light eruption. UVR exposure induces inflammation and infiltration of myeloid cells in UVR exposed skin. Studies in humans and animals demonstrate that CD11b+ myeloid cells clearly play an essential role in UVR-induced immune suppression because UVR does not induce immune suppression when CD11b+ myeloid cells are depleted or when the infiltration of myeloid cells into UVR-exposed skin is reduced. Mechanisms for the development and function of these tolerogenic myeloid cells remain to be fully elucidated. The goal of this application is to determine a role of interleukin-17 (IL-17) in UVR-induced tolerogenic cells and immune suppression. Studies from our group and others have shown that IL-17 is an important cytokine for the infiltration and function of myeloid cells in inflammatory diseases and cancers of the skin. However, little is known about a role of IL-17 in UVR induced immune suppression. Our preliminary studies show that UVR-induced immune suppression and development of regulatory T cells is impaired in mice that are deficient in the receptor for IL-17. Moreover, blockade of IL-17 responses has an inhibitory effect on CD11b+/Gr-1+ myeloid cells in the skin and draining lymph nodes of UVR treated mice, which resemble myeloid derived suppressor cells. Little is known about a role of myeloid derived suppressor cells in UVR induced immune suppression. Our findings for the first time demonstrate that IL-17 has a role in UVR induced immune suppression and specific tolerogenic myeloid cells. Our hypothesis is that IL-17 mediated effect on specific tolerogenic myeloid cells is a mechanism for UVR induced immune tolerance and carcinogenesis. Two specific aims are proposed to test the hypothesis. Aim 1 will determine whether IL-17 mediated development of specific tolerogenic cells is a mechanism for UVR induced regulatory T cells and immune tolerance. We will determine whether specific tolerogenic cells in the skin or draining lymph nodes are responsible for UVR induced immune tolerance and regulatory T cells. Further experiments will examine whether IL-17 mediated effect on UVR induced tolerance is a mechanism for UVR induced skin carcinogenesis. Aim 2 will examine whether IL-17 mediated regulation of specific chemokines and Cox-2/PGE2 in the skin is a mechanism for UVR induced microenvironments for the development of tolerogenic myeloid cells. The long-term goal of our research is to determine mechanisms underlying UVR-induced immune suppression in skin cancer and photodermatological diseases. Targeting IL-17 mediated effects on myeloid cells may provide a novel therapeutic strategy to prevent and treat UVR-induced immune suppression and may have broad implications in skin cancers and diseases, which are caused by environmental hazards.