The systemic effects of ultraviolet radiation: From mast cells and cytokines to protection from CNS-targeted autoimmunity

Excessive exposure to the ultraviolet (UV) wavebands within sunlight makes a substantial contribution to the initiation, progression and metastasis of skin cancer. In contrast, insufficient exposure to these same UV wavebands significantly raises the risk of developing autoimmune diseases like multiple sclerosis (MS). Suppression of the immune system allows skin cancers to establish and grow by evading immunological destruction. At the same time, immune suppression is enormously beneficial in the prevention and treatment of autoimmunity. Being a powerful and potent broad-spectrum immune suppressant, it is hypothesised that UV exerts these apparently incongruous health effects by modulating the development, activation and migration of immune cells. Mast cells are a major target of UV radiation and mediate many of the immunological and carcinogenic effects of sunlight. One way UV modulates the immune system is by altering chemokines to affect the migration of mast cells into and away from UV-exposed skin. Consequently, the skin, lymph nodes, spleen and bone marrow of mice exposed to chronic, immune suppressive doses of UV contain significantly larger numbers of mature mast cells. Exposure to cancer-causing doses of UV radiation affects not just cells and molecules in the skin, but also bone marrow stem cells. To investigate the mechanism by which UV affects the systemic infiltration of tissues by mast cells, C57BL/6 mice were irradiated with solar simulated UV radiation 4 times per week for 16 weeks. At this point, mRNA and protein was isolated from the bone marrow, spinal cord and brain and analysed by real time qRTPCR and ELISA. Unlike its effects on the skin and draining lymph nodes, this UV regime did not alter the CXCR4/CXCR7-CXCL12 chemokine pathway in the bone marrow. CCL5 was found to be significantly downregulated in the bone marrow. CCR1 and CCR3 were found to be expressed on the surface of a small percentage of freshly isolated bone marrow cells. Subsequent addition of recombinant CCL5 to the media led to a rapid and sustained reduction in the numbers of mature mast cells generated. Thus, a UV-induced reduction in CCL5 in the bone marrow would select for cells committed to the mast cell lineage. To investigate this, Lin–c-kit+ Sca-1–Ly6c–CD27–7+T1/ST2+ mast cell progenitors were identified by flow cytometry. Mice exposed to UV had significantly more mast cell progenitors in the bone marrow and peripheral blood. Importantly, mast cells grown from these bone marrow- or blood-derived progenitors were not functionally different to those arising from unirradiated controls. Thus, the increased numbers of mature mast cells seen in the skin and peripheral lymphoid tissues of UV-exposed mice appears to be due, at least in part, to an increase in the production and release of mast cell progenitors. Furthermore, mast cells recruited to peripheral sites of inflammation are not inherently different to those populating resting tissues, but attune themselves and respond to that environment accordingly. In contrast to the bone marrow, CXCL12 was significantly upregulated in the spinal cord of mice chronically exposed to UV. This was the first evidence that UV exposure of the skin can indirectly affect the central nervous system. MOG35-55/CFA-induced experimental autoimmune encephalomyelitis (EAE) was used to further investigate the effects of UV on a disease that targets the spinal cord. C57BL/6 mice were pre-exposed to 7-daily doses of solar simulated UV EAE was induced. Mice continued to receive the UV every 2 days after immunisation for the duration of the experiment. The UV treatment group was significantly protected from EAE disease, displaying less inflammatory foci and less areas of demyelination in the spinal cord at peak disease. Flow cytometry analysis of the spinal cord infiltrates confirmed that the spinal cords of mice exposed to EAE-protecting-UV had significantly lower numbers of B cells, macrophages and activated (CD44hi) T cells (both CD4+ and CD8+). This infiltration was accompanied by increases in the pro-inflammatory cytokine TNF whereas IL-10 was unaffected. Together, these results suggest that UV may be protective from EAE by interfering with the induction of myelin-specific T cells, possibly by activating antigen-specific regulatory cells. However, despite producing significantly higher amounts of IL-10, adoptive transfer of splenocytes or CNS-draining lymph node cells from mice protected from EAE by UV did not confer protection from EAE induction in recipients. These results imply that the cellular and molecular mechanisms by which UV protects internal organs from an immune attack may be different to that which suppresses cutaneous immune responses. Furthermore, if we are to take advantage of the health benefits of UV to suppress an immune attack on internal antigens then we must consider that there is something else about UV exposure apart from, or possibly in addition to, activation of transferrable regulatory cells that explains the protection