Department of Orthopaedics, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
Trauma Emergency Center, The Third Hospital of Hebei Medical University, Shijiazhuang, China.
J Cell Biochem. 2018 Apr;119(4):3081-3090. doi: 10.1002/jcb.26446. Epub 2017 Dec 26.
Spinal cord injury (SCI) is a devastating disease insulting neurological system, and it could be further exacerbated by overwhelming inflammatory responses, where macrophages play a central role. Depending on their heterogeneous phenotypes, macrophages contribute intricately to SCI's pathological processes and functional recovery. Although stimuli like interferons and cytokines are known to regulate their phonotypical transition, it remains elusive which epigenetic programs macrophages engage to complete phenotype shift. We report here that, the treatment of TMP269, a highly selective class IIa HDACs inhibitor, augments the production of pro-inflammatory cytokines in macrophages after SCI, meanwhile, TMP269 also promotes their M1 phenotype activation, which is independent of Th1 or Th2 cytokines. Moreover, TMP269 exacerbates tissue damage and impairs functional recovery after SCI. At last, the adoptive transfer of bone marrow-derived macrophages (BMDMs) overexpressing class IIa HDACs shows beneficial effects in inflammation resolution and functional recovery after SCI. Thus, activating the class IIa HDACs to harness the anti-inflammatory effects of macrophages may represent a potential target to treat SCI.
脊髓损伤（SCI）是一种严重的神经系统疾病，过度的炎症反应会进一步加重 SCI，而巨噬细胞在其中起着核心作用。根据其异质性表型，巨噬细胞在 SCI 的病理过程和功能恢复中起着复杂的作用。尽管干扰素和细胞因子等刺激物已被证实可以调节其表型转变，但巨噬细胞参与完成表型转变的表观遗传程序仍不清楚。我们在这里报告，高度选择性的 IIa 类组蛋白去乙酰化酶（HDACs）抑制剂 TMP269 可增强 SCI 后巨噬细胞中促炎细胞因子的产生，同时，TMP269 还促进其 M1 表型激活，这与 Th1 或 Th2 细胞因子无关。此外，TMP269 加剧 SCI 后的组织损伤并损害功能恢复。最后，过表达 IIa 类 HDACs 的骨髓来源巨噬细胞（BMDMs）的过继转移在 SCI 后炎症消退和功能恢复方面显示出有益作用。因此，激活 IIa 类 HDACs 以利用巨噬细胞的抗炎作用可能代表治疗 SCI 的一个潜在靶点。
