Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy

Aim: In a recent study, O’Brien and colleagues assessed how alterations in brain-derived neurotrophic factor (BDNF) and its transcriptional regulator sirtuin (SIRT1) damaged the Meissner corpuscle, a skin mechanoreceptor, and its innervating Aβ fibers in mouse models of painful diabetic neuropathy.

Methods: Using the high-fat diet model alone or combined with low-dose streptozotocin, neuropathy phenotyping, including behavioral testing, nerve conduction velocity measures, as well as intraepidermal nerve fiber density, subepidermal Aβ fiber density, and Meissner corpuscle quantification was performed. Next, the authors applied single-cell RNA sequencing, western blotting, and fluorometric assays to determine the cellular and molecular events that regulate Meissner corpuscle density and innervation in mouse footpads. They specifically focused on the role of skin- derived BDNF and SIRT1 pathways using cell-specific knockout (KO) or overexpressing models.

Results: The reduced SIRT1 deacetylase activity was accompanied by a decreased BDNF expression and a subsequent loss of Meissner corpuscles and their innervating Aβ fibers in the foot skin of neuropathic animals. SIRT1 deletion in a keratinocyte-specific manner exacerbated mechanical allodynia in diabetic mice, likely due to the aberrant Meissner corpuscle morphology and a retrograde degeneration of the Aβ fibers. A similar event was observed in BDNF KO animals. Conversely, overexpressing SIRT1 in the skin induced Meissner corpuscle reinnervation and regeneration, and improved mechanical sensitivity in diabetic mice.

Conclusions: Together, these findings highlight the importance of skin-derived BDNF and SIRT1 in the maintenance of Meissner corpuscles and the regulation of mechanical allodynia in diabetic neuropathy.

Comments. Diabetic neuropathy, especially distal symmetric polyneuropathy, is predominantly a sensory disorder, based on its clinical manifestation and the progressive degeneration of small sensory fibers observed in both patients and mice. In addition to thermal hyperalgesia, diabetic patients experience mechanical allodynia, which is thought to be triggered by a damage to Aβ fibers and their associated sensory organs, like Meissner corpuscles. The study by O’Brien and colleagues is a key investigation of the neuropathological mechanisms underlying Meissner corpuscle abnormalities and mechanical allodynia in diabetes. It highlights the critical role of the skin microenvironment, particularly BDNF and SIRT1, in preserving Meissner corpuscles and their innervation. The authors also employ elegant in vivo studies to demonstrate that BDNF and SIRT1 regulate mechanical allodynia in diabetic mice with painful neuropathy. Together, these findings suggest that the topical activation of these signaling molecules may be effective in alleviating pain in diabetic patients.

Stéphanie Eid

Reference. O'Brien J, Niehaus P, Chang K, Remark J, Barrett J, Dasgupta A, Adenegan M, Salimian M, Kevas Y, Chandrasekaran K, Kristian T, Chellappan R, Rubin S, Kiemen A, Lu CP, Russell JW, Ho CY. Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy. Brain. 2024 Mar 30:awae100. doi: 10.1093/brain/awae100. Epub ahead of print. PMID: 38554393.

https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awae100/7638192