Eye Institute, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.
Medical School, Nantong University, Nantong, Jiangsu Province, China.
Transl Vis Sci Technol. 2022 Mar 2;11(3):34. doi: 10.1167/tvst.11.3.34.
M1 macrophages can promote corneal allograft rejection (CGR). Inhibiting M1 macrophage polarization by the JAK/STAT1 pathway may be a new strategy to prevent CGR. Tofacitinib, a potent pan-JAK inhibitor, can inhibit JAK/STAT activation. Here, we investigated the inhibitory effects of tofacitinib on M1 macrophage polarization and its therapeutic effect on rat CGR.
Corneal allograft transplantation was performed and administrated with 0.3% tofacitinib in rats. The corneal allografts were assessed clinically. The corneas were detected for M1 macrophages, lymphatic vessels, and inflammatory cytokine expression using immunohistochemistry and real-time polymerase chain reaction (PCR). Dendritic cells (DCs) in ipsilateral cervical lymph nodes were detected by flow cytometry. The effect and mechanism of tofacitinib on macrophages were explored by real-time PCR, enzyme-linked immunoassay, and western blot analysis in vitro.
The results showed that topical administration of 0.3% tofacitinib significantly prolonged corneal graft survival. Tofacitinib-treated corneal allografts displayed a proportionate decrease in M1 macrophages and reduced lymphatic vessel density with fewer DCs in rat ipsilateral cervical lymph nodes. Tofacitinib reduced the mRNA expression of inflammatory cytokines, including iNOS, MCP-1, TNF-α, IL-6, IL-1β, and VEGF-C, and inhibited STAT1 activation in rat corneal grafts. In addition, tofacitinib suppressed M1 macrophage polarization via STAT1 activation after IFN-γ and lipopolysaccharide stimulation in vitro.
Tofacitinib could suppress M1 macrophage polarization and subsequently delay CGR by inhibiting STAT1 activation. The data indicate that tofacitinib is an effective drug for CGR.
This study provided evidence that topical administration of 0.3% tofacitinib may be a novel clinical strategy to prevent CGR.
M1 巨噬细胞可促进角膜同种异体移植物排斥反应（CGR）。通过 JAK/STAT1 通路抑制 M1 巨噬细胞极化可能是预防 CGR 的新策略。托法替尼是一种有效的泛 JAK 抑制剂，可抑制 JAK/STAT 激活。在此，我们研究了托法替尼对 M1 巨噬细胞极化的抑制作用及其对大鼠 CGR 的治疗作用。
在大鼠中进行角膜同种异体移植，并给予 0.3%托法替尼。临床评估角膜移植物。通过免疫组织化学和实时聚合酶链反应（PCR）检测 M1 巨噬细胞、淋巴管和炎症细胞因子的表达。通过流式细胞术检测同侧颈淋巴结中的树突状细胞（DC）。通过实时 PCR、酶联免疫吸附试验和 Western blot 分析体外研究托法替尼对巨噬细胞的作用和机制。
结果表明，局部给予 0.3%托法替尼可显著延长角膜移植物的存活时间。与对照组相比，托法替尼治疗的角膜移植物 M1 巨噬细胞比例降低，淋巴管密度降低，大鼠同侧颈淋巴结中的 DC 减少。托法替尼降低了炎症细胞因子（包括 iNOS、MCP-1、TNF-α、IL-6、IL-1β 和 VEGF-C）的 mRNA 表达，并抑制了大鼠角膜移植物中 STAT1 的激活。此外，托法替尼在体外通过 IFN-γ和脂多糖刺激抑制 STAT1 激活，从而抑制 M1 巨噬细胞极化。
托法替尼可通过抑制 STAT1 激活来抑制 M1 巨噬细胞极化，从而延迟 CGR。数据表明，局部给予 0.3%托法替尼可能是预防 CGR 的一种新的临床策略。
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