Topical Administration of 0.3% Tofacitinib Suppresses M1 Macrophage Polarization and Allograft Corneal Rejection by Blocking STAT1 Activation in the Rat Cornea.

Abstract

PurposeM1 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.MethodsCorneal 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.ResultsThe 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.ConclusionsTofacitinib could suppress M1 macrophage polarization and subsequently delay CGR by inhibiting STAT1 activation. The data indicate that tofacitinib is an effective drug for CGR.Translational RelevanceThis study provided evidence that topical administration of 0.3% tofacitinib may be a novel clinical strategy to prevent CGR.