The Melanocyte and Nerve Fiber Cross‐Talk, Facilitated Also by Semaphorin‐4A, Enhances UV‐B‐Induced Melanogenesis

ABSTRACT Epidermal melanocytes form synaptic‐like contacts with cutaneous nerve fibers, but the functional outcome of these connections remains elusive. In this pilot study we used our fully humanized re‐innervated skin organ culture model to investigate melanocyte‐nerve fiber interactions in UV‐B‐induced melanogenesis. UV‐B‐irradiation significantly enhanced melanin content and tyrosinase activity in re‐innervated skin compared to non‐innervated controls, indicating that neuronal presence is essential for exacerbating pigmentation upon UV‐B irradiation in long‐term culture. Comparative transcriptomic analysis between laser‐capture‐microdissected melanocytes from freshly embedded human skin and published microarray data on in vitro primary melanocytes identified Semaphorin‐4A (SEMA4A) as possible mediator of melanocyte‐nerve fibers interactions. SEMA4A protein levels in Gp100 + ‐epidermal melanocytes were significantly higher in re‐innervated skin, and reduced by UV‐B treatment. Analysis of melanocytes in vitro showed reduced SEMA4A protein expression 24 h after UV‐B‐irradiation while SEMA4A secretion into the medium was increased. Beta‐tubulin expression and axon growth in sensory neurons were stimulated by conditioned media (CM) from UV‐B irradiated melanocytes. When this neuronal‐conditioned medium was transferred to fresh melanocytes, melanin content increased, but only if neurons had been treated with CM from UV‐B irradiated melanocytes. These findings highlight the importance of melanocyte‐neuron interactions for UV‐B‐induced melanogenesis and suggest that secreted proteins (e.g., SEMA4A) can function as a novel target to treat hypo‐ and hyperpigmentation disorders.