JCI|Brett M Morrison团队揭示巨噬细胞MCT1促进小鼠损伤后外周神经再生机制

最新细胞功能及机制文献分享
周围神经具有再生能力,但再生速度缓慢,许多神经损伤会导致患者恢复不完全和永久性残疾。巨噬细胞在外周神经损伤反应中起关键作用,有助于沃勒变性和神经再生,最近已证明它们的功能依赖于细胞内代谢。迄今为止,尚未研究细胞内代谢对周围神经再生的影响。2021年11月1日,美国马里兰州巴尔的摩约翰霍普金斯大学医学院神经内科Brett M Morrison团队在Journal of Clinical Investigation上发表了题为“Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice”的研究论文。在本研究中,团队探讨了Slc16a1基因的MCT1对周围神经再生的影响,结果发现MCT1有助于巨噬细胞代谢、表型和功能,特别是在吞噬作用和周围神经再生方面,证明MCT1在巨噬细胞中具有重要的生物学作用,并且操纵巨噬细胞代谢可以促进周围神经损伤修复。
外周神经损伤可能是外伤、外科治疗、药物或毒素刺激的结果,其修复依赖于受伤的轴突和非神经元细胞(特别是雪旺细胞(SCs)和巨噬细胞)。虽然周围神经系统在受伤后能够再生,但再生速度相当缓慢,人类约为1mm/天,啮齿动物约为3-5mm/天。巨噬细胞不仅在神经变性期间大量存在,而且在神经再生期间也大量存在,其分泌的细胞因子可触发神经中的非神经元细胞的生长因子合成,并产生促进SCs迁移和轴突再生的因子,通过促炎、抗炎或促再生状态的能力为神经初始快速浸润(促炎巨噬细胞占主导地位)和随后的沃勒变性、神经再生和髓鞘再生(促再生巨噬细胞占主导地位)创造了有利的微环境,其还可通过分泌因子影响神经损伤后周围SCs和神经元的代谢。最近,研究人员对巨噬细胞在免疫生物学中的作用进行了探索,已证明单羧酸转运蛋白(MCT),尤其是MCT1对调节多种免疫细胞功能至关重要。
在此项研究中,团队在成功构建具有巨噬细胞选择性MCT1缺失或过表达以及巨噬细胞转移的小鼠模型的基础上,确定了MCT1在巨噬细胞代谢和外周神经损伤反应中的关键免疫作用,发现巨噬细胞特异性MCT1缺失可通过降低巨噬细胞的吞噬能力和抑制受损神经中促再生微环境的形成来破坏轴突再生,这可通过激活ATF3进行调节。重要的是,巨噬细胞中MCT1的上调加速了周围神经损伤后的再生,基于此,团队提出了治疗周围神经损伤的一个潜在的有前景的途径,这是世界范围内没有治疗选择的常见临床问题。
《JCI|Brett M Morrison团队揭示巨噬细胞MCT1促进小鼠损伤后外周神经再生机制》
图 本文图形摘要示意图。

期刊及DOI号

J Clin Invest. 2021 Nov 1. 

doi: 10.1172/JCI141964.

题目

Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice

摘要

Peripheral nerves have the capacity for regeneration, but the rate of regeneration is so slow that many nerve injuries lead to incomplete recovery and permanent disability for patients. Macrophages play a critical role in the peripheral nerve response to injury, contributing to both Wallerian degeneration and nerve regeneration, and their function has recently been shown to be dependent on intracellular metabolism. To date, the impact of their intracellular metabolism on peripheral nerve regeneration has not been studied. We examined conditional transgenic mice with selective ablation in macrophages of solute carrier family 16, member 1 (Slc16a1), which encodes monocarboxylate transporter 1 (MCT1), and found that MCT1 contributed to macrophage metabolism, phenotype, and function, specifically in regard to phagocytosis and peripheral nerve regeneration. Adoptive cell transfer of wild-type macrophages ameliorated the impaired nerve regeneration in macrophage-selective MCT1-null mice. We also developed a mouse model that overexpressed MCT1 in macrophages and found that peripheral nerves in these mice regenerated more rapidly than in control mice. Our study provides further evidence that MCT1 has an important biological role in macrophages and that manipulations of macrophage metabolism can enhance recovery from peripheral nerve injuries, for which there are currently no approved medical therapies.

《JCI|Brett M Morrison团队揭示巨噬细胞MCT1促进小鼠损伤后外周神经再生机制》
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