Toll-like receptors and inflammation in metabolic neuropathy; a role in early versus late disease?
Toll-like receptors and inflammation in metabolic neuropathy; a role in early versus late disease?
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DOI：
10.1016/j.expneurol.2019.112967
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发表时间：
2019-10-01
影响因子：
5.3
通讯作者：
Feldman, E. L.
中科院分区：
文献类型：
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作者：
Elzinga, S.;Murdock, B. J.;Feldman, E. L.
神经病变是代谢综合征、前驱糖尿病和糖尿病的常见、病态并发症。最近的研究表明，免疫系统在神经病变的发展中具有潜在的作用。特别是，toll样受体（TLR）2和4与代谢功能障碍有关，并且阻断TLR 4被提议作为神经性疼痛的治疗。在目前的研究中，我们研究了免疫系统，特别是TLR 2和4，在神经病变的发病机制和进展中的作用。首先分析来自人类和小鼠糖尿病前期和糖尿病神经病变模型的腓肠神经或坐骨神经基因表达阵列，以鉴定KEGG（京都基因和基因组百科全书）数据库中差异表达的TLR 2和TLR 4相关基因。我们观察到与TLR 2和4相关的基因，特别是脂多糖结合蛋白（LPB）和磷脂酰肌醇-4，5-二磷酸3-激酶催化亚基β（PIK 3CB），在不同物种和多种糖尿病前期和糖尿病神经病变小鼠模型中失调。为了进一步理解这些途径在体内的作用，将置于60%高脂肪饮食（HFD-TLR 2/4（-/-））的TLR 2和4整体敲除小鼠与置于高脂肪饮食（HFD-WT）的野生型（WT）小鼠和置于标准饮食（CON）的WT对照进行比较。然后在两个时间点对小鼠进行代谢、神经病和免疫表型分析，以评估TLR信号传导对代谢功能障碍期间神经病和免疫随时间推移的影响。我们发现HFD-TLR 2/4（-/-）和HFD-WT小鼠的体重比CON小鼠重，但空腹血糖水平没有增加。尽管血糖水平正常，但HFD-TLR 2/4（-/-）小鼠最终在较晚的时间点（28周龄）发生神经病，但在较早的时间点（16周龄）在一定程度上免受神经病的影响，如通过较短的后爪缩回时间测量的。这与HFD-WT小鼠形成对比，HFD-WT小鼠在高脂肪饮食的11周内发生神经病，并且在早期和晚期时间点的所有测量值均为神经病性。最后，我们在稍后的时间点对所有三个小鼠组进行免疫表型分析，发现外周血Ly 6C-髓样细胞数量以及F4/80 +表达存在差异。这些结果表明TLR信号可能通过免疫调节和募集影响感觉神经元神经病变的早期发展。
Neuropathy is a common, morbid complication of the metabolic syndrome, prediabetes, and diabetes. Recent studies have indicated a potential role for the immune system in the development of neuropathy. In particular, toll-like receptors (TLR) 2 and 4 have been linked to metabolic dysfunction, and blocking TLR4 is proposed as a treatment for neuropathic pain. In the current study, we investigated the role of the immune system, particularly TLRs 2 and 4, in the pathogenesis and progression of neuropathy. Sural or sciatic nerve gene expression arrays from humans and murine neuropathy models of prediabetes and diabetes were first analyzed to identify differentially expressed TLR2- and TLR4-associated genes within the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. We observed that genes associated with TLRs 2 and 4, particularly lipopolysaccharide binding protein (LPB) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB), were dysregulated across species and across multiple murine models of prediabetic and diabetic neuropathy. To further understand the role of these pathways in vivo, TLR 2 and 4 global knockout mice placed on a 60% high fat diet (HFD-TLR2/4(-/-)) were compared with wild type (WT) mice on a high fat diet (HFD-WT) and WT controls on a standard diet (CON). Mice then underwent metabolic, neuropathic, and immunological phenotyping at two time points to assess the impact of TLR signaling on neuropathy and immunity during metabolic dysfunction over time. We found that HFD-TLR2/4(-/-) and HFD-WT mice weighed more than CON mice but did not have increased fasting blood glucose levels. Despite normal blood glucose levels, HFD-TLR2/4(-/-) mice eventually developed neuropathy at the later time point (28 wks of age) but were somewhat protected from neuropathy at the early time point (16 wks of age) as measured by shorter hind paw withdraw latencies. This is in contrast to HFD-WT mice which developed neuropathy within 11 wks of being placed on a high fat diet and were neuropathic by all measures at both the early and late time points. Finally, we immunophenotyped all three mouse groups at the later time point and found differences in the number of peripheral blood Ly6C-myeloid cells as well as F4/80 + expression. These results indicate that TLR signaling influences early development of neuropathy in sensory neurons, potentially via immune modulation and recruitment.