Niemi Jon P, Filous Angela R, DeFrancesco Alicia, Lindborg Jane A, Malhotra Nisha A, Wilson Gina N, Zhou Bowen, Crish Samuel D, Zigmond Richard E
Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA; School of Biomedical Sciences, Kent State University, Kent, OH, USA.
Exp Neurol. 2017 Oct;296:1-15. doi: 10.1016/j.expneurol.2017.06.020. Epub 2017 Jun 20.
Neuropathy is a major diabetic complication. While the mechanism of this neuropathy is not well understood, it is believed to result in part from deficient nerve regeneration. Work from our laboratory established that gp130 family of cytokines are induced in animals after axonal injury and are involved in the induction of regeneration-associated genes (RAGs) and in the conditioning lesion response. Here, we examine whether a reduction of cytokine signaling occurs in diabetes. Streptozotocin (STZ) was used to destroy pancreatic β cells, leading to chronic hyperglycemia. Mice were injected with either low doses of STZ (5×60mg/kg) or a single high dose (1×200mg/kg) and examined after three or one month, respectively. Both low and high dose STZ treatment resulted in sustained hyperglycemia and functional deficits associated with the presence of both sensory and autonomic neuropathy. Diabetic mice displayed significantly reduced intraepidermal nerve fiber density and sudomotor function. Furthermore, low and high dose diabetic mice showed significantly reduced tactile touch sensation measured with Von Frey monofilaments. To look at the regenerative and injury-induced responses in diabetic mice, neurons in both superior cervical ganglia (SCG) and the 4th and 5th lumbar dorsal root ganglia (DRG) were unilaterally axotomized. Both high and low dose diabetic mice displayed significantly less axonal regeneration in the sciatic nerve, when measured in vivo, 48h after crush injury. Significantly reduced induction of two gp130 cytokines, leukemia inhibitory factor and interleukin-6, occurred in diabetic animals in SCG 6h after injury compared to controls. Injury-induced expression of interleukin-6 was also found to be significantly reduced in the DRG at 6h after injury in low and high dose diabetic mice. These effects were accompanied by reduced phosphorylation of signal transducer and activator of transcription 3 (STAT3), a downstream effector of the gp130 signaling pathway. We also found decreased induction of several gp130-dependent RAGs, including galanin and vasoactive intestinal peptide. Together, these data suggest a novel mechanism for the decreased response of diabetic sympathetic and sensory neurons to injury.
神经病变是糖尿病的一种主要并发症。虽然这种神经病变的机制尚未完全明确，但据信部分是由于神经再生不足所致。我们实验室的研究表明，轴突损伤后动物体内会诱导细胞因子gp130家族产生，且其参与再生相关基因（RAGs）的诱导及条件性损伤反应。在此，我们研究糖尿病患者体内是否会出现细胞因子信号传导减少的情况。使用链脲佐菌素（STZ）破坏胰腺β细胞，导致慢性高血糖。分别给小鼠注射低剂量STZ（5×60mg/kg）或单次高剂量（1×200mg/kg），并分别在3个月或1个月后进行检查。低剂量和高剂量STZ治疗均导致持续性高血糖以及与感觉和自主神经病变相关的功能缺陷。糖尿病小鼠的表皮内神经纤维密度和汗腺运动功能显著降低。此外，低剂量和高剂量糖尿病小鼠用von Frey细丝测量的触觉感觉也显著降低。为了研究糖尿病小鼠的再生和损伤诱导反应，对上颈神经节（SCG）以及第4和第5腰背根神经节（DRG）中的神经元进行单侧轴突切断。在挤压损伤后48小时进行体内测量时，高剂量和低剂量糖尿病小鼠坐骨神经中的轴突再生均显著减少。与对照组相比，损伤后6小时，糖尿病动物的SCG中两种gp130细胞因子（白血病抑制因子和白细胞介素-6）的诱导显著减少。在低剂量和高剂量糖尿病小鼠损伤后6小时，DRG中损伤诱导的白细胞介素-6表达也显著降低。这些效应伴随着信号转导和转录激活因子3（STAT3）磷酸化的减少，STAT3是gp130信号通路的下游效应器。我们还发现几种gp130依赖性RAGs（包括甘丙肽和血管活性肠肽）的诱导减少。总之，这些数据提示了糖尿病交感神经和感觉神经元对损伤反应降低的一种新机制。
