IL4 improves white matter repair after stroke

The repair of white matter damage is of paramount importance for functional recovery after brain injuries.We report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 days after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific PPARγ knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the CNS, which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.脑损伤后白质损伤修复对于功能恢复至关重要。本研究发现白细胞介素4（interleukin-4, IL-4）可促进少突胶质细胞再生与髓鞘再生。缺血性脑损伤后，多种胶质细胞（包括少突胶质细胞谱系细胞）中均可检测到IL-4受体的表达。IL-4基因敲除小鼠在卒中后14天内的白质损伤程度显著加重。与上述发现一致，野生型小鼠卒中后经鼻腔给予IL-4纳米颗粒后，通过组织免疫染色、电子显微镜、弥散张量成像与电生理检测证实，其白质完整性得到改善，长期感觉运动与认知功能缺陷得以缓解。IL-4对髓鞘再生的选择性作用在脱髓鞘离体器官型模型中得到验证。本研究借助原代少突胶质细胞前体细胞（oligodendrocyte progenitor cells, OPCs）、小胶质细胞清除小鼠以及条件性少突胶质细胞前体细胞特异性过氧化物酶体增殖物激活受体γ（PPARγ）基因敲除小鼠，发现IL-4可通过PPARγ通路直接促进少突胶质细胞分化并发挥有益作用。本研究揭示了IL-4在中枢神经系统（central nervous system, CNS）中全新的再生调控作用，这一作用独立于其已知的对小胶质细胞/巨噬细胞或外周淋巴细胞的免疫调节功能。因此，经鼻腔给予IL-4或可成为改善卒中及其他脑损伤患者白质完整性的新型治疗策略。