Lipids in ultraviolet radiation-induced immunomodulation

Abstract

Exposure to the ultraviolet (UV) component of sunlight can have both beneficial and detrimental impacts on human health. Immune suppression is a major risk factor for UV-induced skin cancer development and is predicted to protect from autoimmune diseases. While some molecules and cells involved in UV-induced immune suppression are known, precisely how UV coordinates immune suppression in distant sites remains unclear. As the skin-draining lymph nodes are a critical site where immune cells accumulate and interact, we hypothesised that lymphocyte accumulation is a key event in mediating systemic UV-immune suppression. In addition, UV is known to rapidly induce immune suppressive lipids (particularly platelet-activating factor receptor agonists) in the skin. Our specific hypothesis was that immunomodulatory lipids play a role in, and act as biomarkers of, susceptibility to UV-induced immune suppression. To that end, this thesis aimed to assess the role of UV-modified lipids in mediating immune suppression and to discover novel systemic biomarkers measuring an individual’s susceptibility to UV. Exposing the skin of C57BL/6 mice to a single, immune suppressive dose of solar-simulated UV (ssUV, 8 J/cm2) modulated lipids in both the skin-draining lymph nodes and the circulation 24 hours after exposure. Mass spectrometry analysis of lymph nodes identified increased levels of the lipid chemoattractant sphingosine-1-phosphate (S1P) within skin-draining lymph nodes of mice exposed to ssUV-radiation. This UV-induced increase in S1P lead to a downregulation of its receptor, S1P1, on naïve and central memory T cells. This in turn altered T cell recirculation into the blood and caused skin-draining lymph node hypertrophy. In addition, lipidomics analysis using non-targeted mass spectrometry showed that ssUV upregulated the expression of several lipids in the acylcarnitine, diglyceride, triglyceride, phosphatidylethanolamine and phosphatidylcholine families. The ssUV-induced lymph node lipidome was immune suppressive because addition of lipids extracted from the skin-draining lymph nodes of ssUV-exposed mice to stimulated lymphocytes inhibited T cell proliferation. Mass cytometry imaging of lymph node lipids in combination with imaging mass cytometry of lymph node architecture revealed a preferential localisation of ssUV-modified lipids in T cell zones, suggesting that they may be responsible for preventing T cell proliferation. Hence, ssUV-modulated lipids within the skin-draining lymph nodes interfere with normal T cell migration and inhibit proliferation, indicating that they are important mediators of UV-induced immune suppression. In addition to lymph node lipids, ssUV irradiation of the skin altered circulating immune cells and plasma lipids. Flow cytometry analysis showed that ssUV-induced manipulation of lymphocyte recirculation via the S1P pathway resulted in a significant decrease in circulating naïve and central memory T cells. Independently, ssUV exposure altered the plasma lipidome increasing the levels of 18:1-containing triglycerides. The increase in these lipids were observed in mice susceptible (C57BL/6), but not those resistant (BALB/c), to UV-induced immune suppression. Importantly, these triglycerides could also be identified in human plasma. Together, these data propose circulating T cells and plasma lipids as potential UV biomarkers capable of assessing an individual’s susceptibility to UV-mediated immune suppression. The data presented in this thesis support my hypotheses that ssUV-induced cellular accumulation in the lymph nodes and bioactive lipids are involved in systemic immune suppression. Indeed, this thesis highlights a key role for the interference with normal lymphocyte recirculation and inhibition of T cell proliferation by skin-draining lymph node lipids as novel mechanisms responsible for UV-mediated systemic immune suppression. Together with ssUV-modulation of plasma lipids, these cellular and molecular changes may act as potential systemic UV biomarkers associated with susceptibility to immune suppression. These studies reveal the importance of lipids in UV-modulation of the systemic immune response and provides novel targets for the prevention of skin cancer and/or treatment of autoimmune conditions.