Single Cell Transcriptomics of Mouse Epidermis Reveals a Pivotal Role of Langerhans Cells in Painful Diabetic Neuropathy

Painful diabetic neuropathy (PDN) is one of the most common and intractable complications of diabetes, resulting in remodeling of the cutaneous innervation and neuropathic pain. Accumulating evidence suggests the crucial role epidermal non-neuronal cells for the development of PDN. To understand how epidermal cells communicate with cutaneous afferents and how this communication affects PDN, we performed single-cell RNA sequencing of the epidermis of mice fed a high-fat diet (HFD) for 10 weeks. We captured the gene expression profile of keratinocytes and non-keratinocytes cells, including Langerhans cells (LCs). While LCs have been associated with several inflammatory skin diseases, their role in PDN remains unclear. By comparing the transcriptomic profile of male and female HFD mice to mice fed a regular diet, we have identified relevant pathways for axonal degeneration/regeneration in PDN and putatively involved in neuro-immune communication, such as Semaphorin-Plexin pathways. We have also observed a progressive increase of epidermal LC density in HFD that correlates with pain behavior. Moreover, we have identified a panel of inflammatory molecules released by LCs and potentially involved in the onset and maintenance of PDN. In addition, LCs epidermal density is increased in skin biopsy from PDN patients with painful but no in patients with non-painful diabetic neuropathy. Our results reveal a functional association between LCs and sensory afferent neurons and indicate that the altered neuron-immune communication between LCs and cutaneous afferents might contribute to neuropathic pain in PDN and remodeling of the cutaneous innervation in the skin of PDN in mice and patients. Fundings: R01 NS104295-01; HEAL INTIATIVE S3 R01 NS104295-01; AR077691-01.