Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
Bioinformatics & Biostatistics Core, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2021 Mar 9;118(10). doi: 10.1073/pnas.2013374118.
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 () 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 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 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中的促解决共轭物（CTR）maresin-CTR（MCTR）、保护素-CTR（PCTR）和 resolvin-CTR（RCTR），称为半胱氨酸特异性促解决介质（cys-SPM），每种物质都能促进再生、控制感染并加速炎症消退。在这里，我们寻求 cys-SPM 激活涡虫再生中原始途径的证据，这些途径可能将炎症消退和再生联系起来。在手术切除后，用 MCTR3、PCTR3 或 RCTR3（10 nM）增强涡虫再生，每种物质都用于 RNA 测序。这三种 cys-SPM 都上调了 175 个已知的转录本，其 fold-change > 1.25，且联合错误发现率（FDR）< 0.002，还有 199 个规范途径（FDR < 0.25），包括 NF-κB 途径和人类 TRAF3（肿瘤坏死因子受体相关因子 3）的同源物。三种独立的途径分析都集中在 cys-SPM 上调 TRAF3 上。用人类巨噬细胞，三种 cys-SPM 都以 cAMP-PKA 依赖的方式剂量依赖性地增加 TRAF3 的表达。巨噬细胞中 TRAF3 的过表达增强了白细胞介素-10（IL-10）的表达，并且 IL-10 的吞噬作用也以剂量依赖的方式增加。体内沉默 TRAF3 显著降低了 IL-10 和巨噬细胞的吞噬作用。体内沉默 TRAF3 还减轻了 cys-SPM 在限制渗出液中多形核中性粒细胞方面的作用。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以实现解决中的作用。Cys-SPM 激活 TRAF3 信号是感染性炎症消退和再生的分子组成部分。
