Analysis of the immune response to sciatic nerve injury identifies efferocytosis as a key mechanism of nerve debridement.
Analysis of the immune response to sciatic nerve injury identifies efferocytosis as a key mechanism of nerve debridement.
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DOI：
10.7554/elife.60223
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发表时间：
2020-12-02
期刊：
影响因子：
7.7
通讯作者：
Giger RJ
中科院分区：
文献类型：
--
作者：
Kalinski AL;Yoon C;Huffman LD;Duncker PC;Kohen R;Passino R;Hafner H;Johnson C;Kawaguchi R;Carbajal KS;Jara JS;Hollis E;Geschwind DH;Segal BM;Giger RJ
坐骨神经挤压伤会在远端神经和背根神经节(DRGs)内引发无菌炎症。粒细胞和促炎症的Ly6Chigh单核细胞首先侵入神经，并迅速让位于Ly6C阴性的炎症溶解巨噬细胞。在切断的背根节中，检测到少量的血源性白细胞，驻留的巨噬细胞获得分枝状形态。损伤坐骨神经的单细胞RNA测序确定了五个巨噬细胞亚群、修复雪旺细胞和间充质前体细胞。神经挤压部位的巨噬细胞与沃勒变性相关的巨噬细胞在分子上是不同的。在受损的神经中，巨噬细胞‘吃掉’凋亡的白细胞，这一过程被称为胞吐作用，从而促进了抗炎环境。损伤神经中的髓样细胞强烈表达细胞因子GM-CSF的受体，而不是轴突切断的背根节。在GM-CSF缺陷(CSF2-/-)小鼠，炎症消退延迟，条件性损伤诱导的DRG神经元中央轴突再生被取消。因此，条件性损伤诱导的神经修复需要精心协调的神经炎症消退。
Sciatic nerve crush injury triggers sterile inflammation within the distal nerve and axotomized dorsal root ganglia (DRGs). Granulocytes and pro-inflammatory Ly6Chigh monocytes infiltrate the nerve first and rapidly give way to Ly6Cnegative inflammation-resolving macrophages. In axotomized DRGs, few hematogenous leukocytes are detected and resident macrophages acquire a ramified morphology. Single-cell RNA-sequencing of injured sciatic nerve identifies five macrophage subpopulations, repair Schwann cells, and mesenchymal precursor cells. Macrophages at the nerve crush site are molecularly distinct from macrophages associated with Wallerian degeneration. In the injured nerve, macrophages ‘eat’ apoptotic leukocytes, a process called efferocytosis, and thereby promote an anti-inflammatory milieu. Myeloid cells in the injured nerve, but not axotomized DRGs, strongly express receptors for the cytokine GM-CSF. In GM-CSF-deficient (Csf2-/-) mice, inflammation resolution is delayed and conditioning-lesion-induced regeneration of DRG neuron central axons is abolished. Thus, carefully orchestrated inflammation resolution in the nerve is required for conditioning-lesion-induced neurorepair.