Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.
Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.
复制标题
皮肤角质细胞衍生的 SIRT1 和 BDNF 调节糖尿病神经病变小鼠模型中的机械异常性疼痛。
DOI：
10.1101/2023.01.24.523981
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Lu,C
中科院分区：
文献类型：
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作者：
O'Brien,Jennifer;Niehaus,Peter;Chang,Koping;Remark,Juliana;Barrett,Joy;Dasgupta,Abhishikta;Adenegan,Morayo;Salimian,Mohammad;Kevas,Yanni;Chandrasekaran,Krish;Kristian,Tibor;Chellappan,Rajeshwari;Rubin,Samuel;Kiemen,Ashley;Lu,C
糖尿病性神经病变是一种以自发性和机械性异常性疼痛为特征的衰弱性疾病。皮肤机械感受器在机械性异痛症发生中的作用尚不清楚。我们发现患有糖尿病神经病变的小鼠足部皮肤sirtuin 1 （SIRT1）去乙酰化酶活性降低，导致脑源性神经营养因子（BDNF）表达减少，随后迈斯纳小体（一种表达BDNF受体TrkB的机械受体）的神经支配丧失。当SIRT1从皮肤中消失时，糖尿病神经病变小鼠的机械异常性疼痛恶化，可能是由于支配Aβ轴突的迈斯纳小体的逆行变性和迈斯纳小体的异常形成，这可能增加了机械敏感性。在皮肤角质形成细胞特异性BDNF敲除小鼠中也发现了同样的现象。此外，SIRT1在皮肤中的过表达可诱导迈斯纳小体的再神经支配和再生，从而显著改善糖尿病性机械异常性疼痛。总的来说，研究结果表明，皮肤来源的SIRT1和BDNF在皮肤感觉器官再生中的作用是相同的，并强调了开发局部SIRT1激活化合物作为糖尿病机械性异常性疼痛的新治疗方法的潜力。
Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aβ axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia.Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.