Injury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response.

对中枢神经系统的损伤会引发不受控制的炎症反应，从而导致组织修复和破坏。在这里，我们表明，在啮齿动物和人类中，脊髓损伤触发了外周血骨髓细胞上CD95配体（CD95L，FasL）的表面表达。这些细胞上CD95的CD95L刺激通过Syk激酶的募集和激活激活了磷酸肌醇3激酶（PI3K）和金属蛋白酶9（MMP-9），最终导致迁移增加。注射巯基乙酸盐后，髓样细胞中唯一的CD95L缺失大大减少了浸润受损脊髓或发炎腹膜的嗜中性粒细胞和巨噬细胞的数量。重要的是，在神经细胞上，髓系CD95L的缺失而不是CD95的缺失导致脊髓损伤动物的功能恢复。我们的结果表明CD95L作用于外周骨髓细胞以诱导组织损伤。因此，CD95L的中和应被认为是产生受控的有益炎症反应的手段。