The University of Queensland, School of Biomedical Sciences, QLD 4072, Australia.
Exp Neurol. 2013 Sep;247:226-40. doi: 10.1016/j.expneurol.2013.05.002. Epub 2013 May 9.
Macrophages in the injured spinal cord originate from resident microglia and blood monocytes. Whether this diversity in origins contributes to their seemingly dual role in immunopathology and repair processes has remained poorly understood. Here we took advantage of Cx₃cr1(gfp) mice to visualise monocyte-derived macrophages in the injured spinal cord via adoptive cell transfer and bone marrow (BM) chimera approaches. We show that the majority of infiltrating monocytes at 7 days post-injury originate from the spleen and only to a lesser extent from the BM. Prevention of early monocyte infiltration via splenectomy was associated with improved recovery at 42 days post-SCI. In addition, an increased early presence of infiltrating monocytes/macrophages, as a result of CX₃CR1 deficiency within the peripheral immune compartment, correlated with worsened injury outcomes. Adoptive transfer of identified Cx₃cr1(gfp/+) monocytes confirmed peak infiltration at 7 days post-injury, with inflammatory (Ly6C(high)) monocytes being most efficiently recruited. Focal SCI also changed the composition of the two major monocyte subsets in the blood, with more Ly6C(high) cells present during peak recruitment. Adoptive transfer experiments further suggested high turnover of inflammatory monocytes in the spinal cord at 7 days post-injury. Consistent with this, only a small proportion of infiltrating cells unequivocally expressed polarisation markers for pro-inflammatory (M1) or alternatively activated (M2) macrophages at this time point. Our findings offer new insights into the origins of monocyte-derived macrophages after SCI and their contribution to functional recovery, providing a basis for further scrutiny and selective targeting of Ly6C(high) monocytes to improve outcomes from neurotraumatic events.
损伤脊髓中的巨噬细胞来源于固有小胶质细胞和血液单核细胞。这种起源的多样性是否有助于其在免疫病理学和修复过程中看似双重作用，仍知之甚少。在这里，我们利用 Cx₃cr1(gfp) 小鼠通过过继细胞转移和骨髓（BM）嵌合体方法来可视化损伤脊髓中的单核细胞衍生的巨噬细胞。我们表明，7 天损伤后浸润的大多数单核细胞来源于脾脏，而仅从 BM 中较少程度地来源于 BM。通过脾切除术预防早期单核细胞浸润与 SCI 后 42 天的恢复改善相关。此外，由于外周免疫区室中 CX₃CR1 的缺失，浸润的单核细胞/巨噬细胞的早期存在增加，与损伤结果恶化相关。鉴定的 Cx₃cr1(gfp/+)单核细胞的过继转移证实了损伤后 7 天的高峰浸润，其中炎症（Ly6C(high))单核细胞被最有效地募集。局灶性 SCI 还改变了血液中两个主要单核细胞亚群的组成，在招募高峰时存在更多的 Ly6C(high)细胞。过继转移实验进一步表明，7 天损伤后脊髓中的炎症单核细胞周转率高。与此一致的是，此时只有一小部分浸润细胞明确表达了促炎（M1）或替代激活（M2）巨噬细胞的极化标记物。我们的研究结果为 SCI 后单核细胞衍生的巨噬细胞的起源及其对功能恢复的贡献提供了新的见解，为进一步研究和选择性靶向 Ly6C(high)单核细胞以改善神经创伤性事件的结果提供了依据。
