Department of Orthopedics, Shuyang Hospital Affiliated to Medical College of Yangzhou University, Shuyang Hospital of Traditional Chinese Medicine, Shuyang 223600, China; Department of Orthopedics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221004, China.
Department of Orthopedics, Shuyang Hospital Affiliated to Medical College of Yangzhou University, Shuyang Hospital of Traditional Chinese Medicine, Shuyang 223600, China.
Neurosci Lett. 2022 Jan 18;768:136374. doi: 10.1016/j.neulet.2021.136374. Epub 2021 Nov 28.
Macrophage-dominated inflammation by the activation of Toll-like receptor (TLR) pathway leads to neurological disruption after spinal cord injury (SCI). Regulator of G-protein signaling 1 (RGS1) is reported to be a regulator in inflammation. The present study thus purposes to identify the unknown role of RGS1 mediating TLR on inflammation post SCI. A mouse model of traumatic SCI was established by a mechanical trauma at T10. The mice underwent SCI and a macrophage line activated by lipopolysaccharide (LPS) were treated with shRNA-RGS1 to elucidate the role of RGS1 in inflammatory progression. The inflammatory factors were measured, and the degree of histology and function protection were determined. The expression levels of RGS1, myeloid differentiation primary response protein 88 (Myd88), (TIR-domain-containing adaptor inducing interferon-β (TRIF), p38, metalloproteinase (MMP)-2, and MMP-9 were determined. RGS1 was robustly increased both in LPS-activated macrophage and SCI mice. The TLR signaling pathway-induced inflammation was suppressed by RGS1 knockdown. shRNA-mediated silence of RGS1 was exhibited a prominent decrease in TNF-α, IL-1β and IL-6 via TLR/TRIF/ nuclear factor kappa-B (NF-κB) axis. Depletion of RGS1 also inhibited MMP-induced tissue degradation via MAPK-p38 pathway in SCI mice. Moreover, suppression of RGS1 improved spinal cord histology and function recovery. These findings suggest that RGS1 regulates inflammation and tissue disruption via TLR/TRIF/NF-κB signaling pathway in mice with SCI, thereby explaining a novel target that regulates macrophage inflammation post SCI.
小胶质细胞激活 Toll 样受体（TLR）通路引发的炎症反应导致脊髓损伤（SCI）后的神经功能障碍。G 蛋白信号调节因子 1（RGS1）被报道为炎症反应的调节因子。本研究旨在确定 RGS1 在 SCI 后通过 TLR 介导炎症反应的未知作用。通过 T10 处的机械创伤建立外伤性 SCI 小鼠模型。对 SCI 小鼠和脂多糖（LPS）激活的巨噬细胞系进行 shRNA-RGS1 处理，以阐明 RGS1 在炎症进展中的作用。测量炎症因子的水平，并确定组织学和功能保护的程度。检测 RGS1、髓样分化初级反应蛋白 88（Myd88）、（TIR 结构域包含衔接蛋白诱导干扰素-β（TRIF）、p38、基质金属蛋白酶（MMP）-2 和 MMP-9 的表达水平。LPS 激活的巨噬细胞和 SCI 小鼠中 RGS1 的表达均显著增加。RGS1 敲低抑制 TLR 信号通路诱导的炎症。shRNA 介导的 RGS1 沉默通过 TLR/TRIF/核因子 kappa-B（NF-κB）轴显示 TNF-α、IL-1β 和 IL-6 的表达显著降低。在 SCI 小鼠中，RGS1 的耗竭也通过 MAPK-p38 通路抑制 MMP 诱导的组织降解。此外，抑制 RGS1 可改善脊髓组织学和功能恢复。这些发现表明，RGS1 通过 TLR/TRIF/NF-κB 信号通路调节 SCI 小鼠中的炎症和组织破坏，从而为调节 SCI 后巨噬细胞炎症提供了一个新的靶点。
