Groh Janos, Klein Ines, Hollmann Claudia, Wettmarshausen Jennifer, Klein Dennis, Martini Rudolf
Department of Neurology, Developmental Neurobiology, University Hospital Wuerzburg, Wuerzburg.
Glia. 2015 Jun;63(6):977-86. doi: 10.1002/glia.22796. Epub 2015 Jan 27.
We investigated connexin 32 (Cx32)-deficient mice, a model for the X-linked form of Charcot-Marie-Tooth neuropathy (CMT1X), regarding the impact of low-grade inflammation on Schwann cell phenotype. Whereas we previously identified macrophages as amplifiers of the neuropathy, we now explicitly focus on the impact of the phagocytes on Schwann cell dedifferentiation, a so far not-yet addressed disease-related mechanism for CMT1X. Using mice heterozygously deficient for Cx32 and displaying both Cx32-positive and -negative Schwann cells in one and the same nerve, we could demonstrate that macrophage clusters rather than single macrophages precisely associate with mutant but not with Cx32-positive Schwann cells. Similarly, in an advanced stage of Schwann cell perturbation, macrophage clusters were strongly associated with NCAM- and L1-positive, dedifferentiated Schwann cells. To clarify the role of macrophages regarding Schwann cell dedifferentiation, we generated Cx32-deficient mice additionally deficient for the macrophage-directed cytokine colony-stimulating factor (CSF)-1. In the absence of CSF-1, Cx32-deficient Schwann cells not only showed the expected amelioration in myelin preservation but also failed to upregulate the Schwann cell dedifferentiation markers NCAM and L1. Another novel and unexpected finding in the double mutants was the retained activation of ERK signaling, a pathway which is detrimental for Schwann cell homeostasis in myelin mutant models. Our findings demonstrate that increased ERK signaling can be compatible with the maintenance of Schwann cell differentiation and homeostasis in vivo and identifies CSF-1-activated macrophages as crucial mediators of detrimental Schwann cell dedifferentiation in Cx32-deficient mice.
我们研究了连接蛋白32（Cx32）缺陷小鼠，这是一种X连锁型夏科-马里-图斯神经病变（CMT1X）的模型，以探讨低度炎症对雪旺细胞表型的影响。尽管我们之前已确定巨噬细胞是神经病变的放大器，但现在我们明确关注吞噬细胞对雪旺细胞去分化的影响，这是迄今为止CMT1X尚未涉及的与疾病相关的机制。利用杂合性缺乏Cx32且在同一神经中同时存在Cx32阳性和阴性雪旺细胞的小鼠，我们能够证明巨噬细胞簇而非单个巨噬细胞与突变型雪旺细胞精确关联，而不与Cx32阳性雪旺细胞关联。同样，在雪旺细胞扰动的晚期，巨噬细胞簇与神经细胞黏附分子（NCAM）和L1阳性、去分化的雪旺细胞密切相关。为了阐明巨噬细胞在雪旺细胞去分化中的作用，我们培育了同时缺乏巨噬细胞导向细胞因子集落刺激因子（CSF）-1的Cx32缺陷小鼠。在缺乏CSF-1的情况下，Cx32缺陷的雪旺细胞不仅在髓鞘保存方面有预期的改善，而且未能上调雪旺细胞去分化标志物NCAM和L1。双突变体中的另一个新的意外发现是细胞外信号调节激酶（ERK）信号通路的持续激活，该通路在髓鞘突变模型中对雪旺细胞稳态有害。我们的研究结果表明，增加的ERK信号传导在体内可能与雪旺细胞分化和稳态的维持相容，并确定CSF-1激活的巨噬细胞是Cx32缺陷小鼠中有害雪旺细胞去分化的关键介质。
