The recently elucidated proresolving conjugates in tissue regeneration (CTR) maresin-CTR (MCTR), protectin-CTR (PCTR), and resolvin-CTR (RCTR), termed cysteinyl-specialized proresolving mediators (cys-SPMs) each promotes regeneration, controls infection, and accelerates resolution of inflammation. Here, we sought evidence for cys-SPM activation of primordial pathways in planaria (Dugesia japonica) regeneration that might link resolution of inflammation and regeneration. On surgical resection, planaria regeneration was enhanced with MCTR3, PCTR3, or RCTR3 (10 nM), each used for RNA sequencing. The three cys-SPMs shared up-regulation of 175 known transcripts with fold-change > 1.25 and combined false discovery rate (FDR) < 0.002, and 199 canonical pathways (FDR < 0.25), including NF-κB pathways and an ortholog of human TRAF3 (TNFR-associated factor 3). Three separate pathway analyses converged on TRAF3 up-regulation by cys-SPMs. With human macrophages, three cys-SPMs each dose-dependently increased TRAF3 expression in a cAMP-PKA–dependent manner. TRAF3 overexpression in macrophages enhanced Interleukin-10 (IL-10) and phagocytosis of Escherichia coli. IL-10 also increased phagocytosis in a dose-dependent manner. Silencing of mouse TRAF3 in vivo significantly reduced IL-10 and macrophage phagocytosis. TRAF3 silencing in vivo also relieved cys-SPMs’ actions in limiting polymorphonuclear neutrophil in E. coli exudates. These results identify cys-SPM–regulated pathways in planaria regeneration, uncovering a role for TRAF3/IL-10 in regulating mammalian phagocyte functions in resolution. Cys-SPM activation of TRAF3 signaling is a molecular component of both regeneration and resolution of infectious inflammation.

最近阐明的组织再生 (CTR) 中的促分解偶联物 maresin-CTR (MCTR)、保护素-CTR (PCTR) 和分解素-CTR (RCTR)，称为半胱氨酰特化促分解介质 (cys-SPM)，每一种都促进再生，控制感染, 并加速炎症消退。在这里，我们寻找 cys-SPM 激活涡虫原始途径的证据（Dugesia japonica) 可能将炎症消退和再生联系起来的再生。在手术切除时，涡虫再生被 MCTR3、PCTR3 或 RCTR3 (10 nM) 增强，每个都用于 RNA 测序。三个 cys-SPM 共享 175 个已知转录本的上调，倍数变化 > 1.25 且组合错误发现率 (FDR) < 0.002，以及 199 个规范途径 (FDR < 0.25)，包括 NF-κB 途径和人类直向同源物TRAF3（TNFR 相关因子 3）。三个独立的通路分析集中在 cys-SPM 对 TRAF3 的上调上。对于人类巨噬细胞，三种 cys-SPM 均以 cAMP-PKA 依赖性方式剂量依赖性地增加 TRAF3 表达。TRAF3 在巨噬细胞中的过表达增强了白细胞介素 10 (IL-10) 和大肠杆菌的吞噬作用. IL-10 还以剂量依赖性方式增加吞噬作用。体内小鼠 TRAF3 的沉默显着降低了 IL-10 和巨噬细胞的吞噬作用。体内 TRAF3 沉默也减轻了 cys-SPM 在限制大肠杆菌渗出液中多形核中性粒细胞的作用。这些结果确定了涡虫再生中 cys-SPM 调节的途径，揭示了 TRAF3/IL-10 在调节哺乳动物吞噬细胞功能中的作用。TRAF3 信号转导的 Cys-SPM 激活是感染性炎症再生和消退的分子组成部分。