Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037
Proc Natl Acad Sci U S A. 2020 May 19;117(20):11126-11135. doi: 10.1073/pnas.1920935117. Epub 2020 May 5.
While several studies have shown that hypoxic preconditioning suppresses development of the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), no one has yet examined the important clinically relevant question of whether mild hypoxia can impact the progression of preexisting disease. Using a relapsing-remitting model of EAE, here we demonstrate that when applied to preexisting disease, chronic mild hypoxia (CMH, 10% O) markedly accelerates clinical recovery, leading to long-term stable reductions in clinical score. At the histological level, CMH led to significant reductions in vascular disruption, leukocyte accumulation, and demyelination. Spinal cord blood vessels of CMH-treated mice showed reduced expression of the endothelial activation molecule VCAM-1 but increased expression of the endothelial tight junction proteins ZO-1 and occludin, key mechanisms underlying vascular integrity. Interestingly, while equal numbers of inflammatory leukocytes were present in the spinal cord at peak disease (day 14 postimmunization; i.e., 3 d after CMH started), apoptotic removal of infiltrated leukocytes during the remission phase was markedly accelerated in CMH-treated mice, as determined by increased numbers of monocytes positive for TUNEL and cleaved caspase-3. The enhanced monocyte apoptosis in CMH-treated mice was paralleled by increased numbers of HIF-1α+ monocytes, suggesting that CMH enhances monocyte removal by amplifying the hypoxic stress manifest within monocytes in acute inflammatory lesions. These data demonstrate that mild hypoxia promotes recovery from preexisting inflammatory demyelinating disease and suggest that this protection is primarily the result of enhanced vascular integrity and accelerated apoptosis of infiltrated monocytes.
虽然已有几项研究表明，低氧预处理可抑制多发性硬化症（MS）实验性自身免疫性脑脊髓炎（EAE）模型的发展，但尚未有人研究轻度低氧是否会影响已存在疾病的进展这一重要临床相关问题。我们采用 EAE 缓解-复发模型，证明了在已存在疾病的情况下，慢性轻度低氧（CMH，10%O）可明显加速临床恢复，导致临床评分长期稳定降低。在组织学水平，CMH 导致血管破坏、白细胞积累和脱髓鞘显著减少。CMH 治疗小鼠的脊髓血管显示内皮激活分子 VCAM-1 的表达减少，而内皮紧密连接蛋白 ZO-1 和闭合蛋白的表达增加，这是血管完整性的关键机制。有趣的是，虽然在疾病高峰期（免疫后 14 天，即 CMH 开始后 3 天）脊髓中有相同数量的炎症性白细胞，但在 CMH 治疗小鼠中，在缓解期浸润白细胞的凋亡清除明显加速，这通过增加 TUNEL 和 cleaved caspase-3 阳性的单核细胞数量来确定。CMH 治疗小鼠中单核细胞凋亡的增强与 HIF-1α+单核细胞数量的增加平行，表明 CMH 通过放大急性炎症病变中单核细胞内的缺氧应激来增强单核细胞的清除。这些数据表明，轻度低氧可促进已存在的炎症性脱髓鞘疾病的恢复，并表明这种保护主要是由于血管完整性增强和浸润单核细胞的凋亡加速所致。
