Mast Cell Migration from the Skin to the Draining Lymph Nodes upon Ultraviolet Irradiation Represents a Key Step in the Induction of Immune Suppression

Abstract

The UV radiation in sunlight is the primary cause of skin cancer. UV is also immunosuppressive and numerous studies have shown that UV-induced immune suppression is a major risk factor for skin cancer induction. Previous studies demonstrated that dermal mast cells play a critical role in the induction of immune suppression. Mast cell-deficient mice are resistant to the immunosuppressive effects of UV radiation, and UV-induced immune suppression can be restored by injecting bone marrow-derived mast cells into the skin of mast cell- deficient mice. The exact process however, by which mast cells contribute to immune suppression, is not known. In this study, we show that one of the first steps in the induction of immune suppression is mast cell migration from the skin to the draining lymph nodes. UV exposure, in a dose-dependent manner, causes a significant increase in lymph node mast cell numbers. When GFP+ skin was grafted onto mast cell-deficient mice, we found that GFP+ mast cells preferentially migrated into the lymph nodes draining the skin. The mast cells migrated primarily to the B cell areas of the draining nodes. Mast cells express CXCR4+ and UV exposure up-regulated the expression of its ligand CXCL12 by lymph node B cells. Treating UV-irradiated mice with a CXCR4 antagonist blocked mast cell migration and abrogated UV-induced immune suppression. Our findings indicate that UV-induced mast cell migration to draining lymph nodes, mediated by CXCR4 interacting with CXCL12, represents a key early step in UV-induced immune suppression.

The Immune-Modulating Cytokine and Endogenous Alarmin Interleukin-33 Is Upregulated in Skin Exposed to Inflammatory UVB Radiation

“…In some experiments, the fluorescently labeled sections were photographed immediately before the removal of the coverslip and subsequent staining of mast cells using toluidine blue as we have described. 42 For the simultaneous immunofluorescence detection of IL-33 with CD45 or CD117, slides were first labeled for IL-33 as above, substituting the biotin-labeled detecting antibody for a chicken anti-goat Alexa Fluor 488 (Molecular Probes). These slides were then washed and biotin blocked as above before being incubated for 2 hours at 37°C with 10 g/mL of BD Biosciences clone 30-F11 (for CD45), 10 g/mL Biolegend clone 2B8 (for CD117), or 10 g/mL of eBioscience rat IgG 2b isotype control.…”

“…Cycle threshold (C T ) values for IL-33 were normalized to GAPDH or HPRT and analyzed with Rotor-Gene 6.0 software (Corbett Research, NSW, Australia), as we have previously described. 42 …”

Photohardening of polymorphic light eruption patients decreases baseline epidermalLangerhans cell density while increasing mast cell numbers in the papillary dermis

“…Although traditionally associated with atopy, mast cells accumulate at sites of acute (12) and chronic (13) sun exposure in humans and have the capacity to induce immunological tolerance (14). Murine studies have revealed that mast cells are likely to play an important pathological role in the development and growth of UV-induced skin cancers (15), presumably by transmitting the suppressive signal generated in UV-irradiated murine skin to the immune system (16). Importantly, interfering with mast cell migration into and away from the skin also protects from UV-induced skin cancer (17).…”

Homeostatic Role of Transforming Growth Factor-β in the Oral Cavity and Esophagus of Mice and Its Expression by Mast Cells in These Tissues

“…Although mast cells are classically thought to be involved in the initiation and potentiation of allergic and anaphylatic responses, 43 recent studies have also demonstrated that mast cells can contribute to immunosuppression under a variety of conditions, including contact hypersensitivity reactions or inflammation after exposure to UV irradiation, 44 immunosuppression in the skin after UV irradiation, 45 glomerulonephritis, 46 and the induction of tolerance in a model of skin transplantation. 47 IL-10 production by mast cells was found to be a critical factor for limiting contact hypersensitivity inflammatory responses, 44 but to our knowledge TGF-␤ production by mast cells has not yet been demonstrated to participate in these immunosuppressive activities.…”