CLEC12B regulates melanocyte immunity and homeostasis in the skin through the STAT1/IRF1 axis.

CLEC12B is a C-type lectin receptor involved in the inhibition of natural killers-mediated cytotoxicity. We have previously shown that CLEC12B is predominantly expressed on melanocytes, inhibits melanin production and pigmentation as well as proliferation of melanoma. To date, the role of CLEC12B in skin immunity is unknown. Upon phosphorylation of its immunoreceptor tyrosine-based inhibitory motif, we demonstrate that CLEC12B increases the production of innate chemokines from human melanocytes through the activation of the signal transducer and activator of transcription 1 (STAT-1)/interferon regulatory factor 1 (IRF-1)-mediated IFNγ pathway, resulting in chemoattraction of immune cells. We have demonstrated CLEC12B to potentiate the effect of IFNγ in primed melanocytes. Furthermore, CLEC12B recognizes cutaneous (Staphylococcus aureus and Escherichia coli) but not gut (Listeria monocytogenes) bacteria and is capable of modulating their chemokine responses. Finally, we have shown that CLEC12B senses motifs present on human melanocytes and fibroblasts but not keratinocytes. Together, these results demonstrate that CLEC12B plays an important function in the human skin, bridging innate and adaptative immunity. This mechanism is of great interest as IFNγ and cellular recruitment are key initial steps involved in inflammation of many skin pathologies, making this receptor an interesting therapeutic target.