Neuroscience Graduate Program, The Ohio State University, Columbus, OH, USA; Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Belford Center for Spinal Cord Injury, Center for Brain and Spinal Cord Repair, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Belford Center for Spinal Cord Injury, Center for Brain and Spinal Cord Repair, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
Exp Neurol. 2022 Sep;355:114114. doi: 10.1016/j.expneurol.2022.114114. Epub 2022 May 11.
Glucocorticoid receptors (GRs), part of the nuclear receptor superfamily of transcription factors (TFs), are ubiquitously expressed in all cell types and regulate cellular responses to glucocorticoids (e.g., cortisol in humans; corticosterone in rodents). In myeloid cells, glucocorticoids binding to GRs can enhance or repress gene transcription, thereby imparting distinct and context-dependent functions in macrophages at sites of inflammation. In experimental models and in humans, glucocorticoids are widely used as anti-inflammatory treatments to promote recovery of function after SCI. Thus, we predicted that deleting GR in mouse myeloid lineage cells (i.e., microglia and monocyte-derived macrophages) would enhance inflammation at the site of injury and worsen functional recovery after traumatic spinal cord injury (SCI). Contrary to our prediction, the intraspinal macrophage response to a moderate (75 kdyne) spinal contusion SCI was reduced in Cxcr1-Cre;GR conditional knockout mice (with GR specifically deleted in myeloid cells). This phenotype was associated with improvements in hindlimb motor recovery, myelin sparing, axon sparing/regeneration, and microvascular protection/plasticity relative to SCI mice with normal myeloid cell GR expression. Further analysis revealed that macrophage GR deletion impaired lipid and myelin phagocytosis and foamy macrophage formation. Together, these data reveal endogenous GR signaling as a key pathway that normally inhibits mechanisms of macrophage-mediated repair after SCI.
糖皮质激素受体（GRs）是核受体转录因子（TFs）超家族的一部分，在所有细胞类型中广泛表达，调节细胞对糖皮质激素（如人类的皮质醇；啮齿动物的皮质酮）的反应。在髓样细胞中，糖皮质激素与 GR 结合可以增强或抑制基因转录，从而在炎症部位的巨噬细胞中赋予独特且依赖于背景的功能。在实验模型和人类中，糖皮质激素被广泛用作抗炎治疗药物，以促进 SCI 后功能的恢复。因此，我们预测在小鼠髓样细胞系（即小胶质细胞和单核细胞衍生的巨噬细胞）中删除 GR 会加重损伤部位的炎症，并使创伤性脊髓损伤（SCI）后的功能恢复恶化。与我们的预测相反，在 Cxcr1-Cre 中，中度（75 kdyne）脊髓挫伤 SCI 后的脊髓内巨噬细胞反应；GR 条件性敲除小鼠（髓样细胞中特异性缺失 GR）减少。这种表型与后肢运动恢复、髓鞘保存、轴突保存/再生以及微血管保护/可塑性的改善相关，与具有正常髓样细胞 GR 表达的 SCI 小鼠相比。进一步的分析表明，巨噬细胞 GR 缺失会损害脂质和髓鞘的吞噬作用以及泡沫状巨噬细胞的形成。综上所述，这些数据揭示了内源性 GR 信号作为一种关键途径，通常抑制 SCI 后巨噬细胞介导的修复机制。
