Abstract：
Directing immunometabolism presents new opportunities to modulate key cell types associated with the formation of foreign body response (FBR) capsule. Contrasting approaches directing immunometabolism are investigated to mitigate FBR: a broadly suppressive metabolic inhibitor (MI) cocktail comprised of 2-deoxyglucose (2-DG), metformin, and 6-diazo-5-oxo-l-norleucine (DON) with daily systemic dosing regimen, and local weekly injection of the more narrowly focused tryptophan catabolizing IDO-Gal3 fusion protein. Treatments significantly decrease FBR capsule formed around subcutaneously implanted cellulose disks. MI cocktail results in a substantially thinner FBR capsule (40% of control), while weekly local injection of IDO-Gal3 also results in a thinner FBR capsule (69% of control). RNA-sequencing capsule transcripts reveal MI cocktail promotes quiescence, with decreased antigen processing and presentation, T helper subset differentiation, and cytokine-cytokine receptor pathway. IDO-Gal3 promotes pro-regenerative, alternatively activated M2-like macrophages and T helper 2 cells, with increased expression of type 2 response-associated genes (Il4, Il13, Arg1, Mrc1, Chil3, Gata3). IDO-Gal3 decreases pro-inflammatory innate sensing pathways, and C-type lectin receptor, NOD-like receptor, RIG-I-like receptor, and Toll-like receptor signaling. This work helps define key gene targets and pathways concomitantly regulated in the FBR capsule during immunometabolic modulation compared to control FBR capsule.
摘要：
指导免疫代谢为调节与异物反应（FBR）胶囊形成相关的关键细胞类型提供了新的机会。研究了指导免疫代谢的对比方法以减轻FBR：由2-脱氧葡萄糖（2-DG）组成的广泛抑制性代谢抑制剂（MI）混合物，二甲双胍,和6-重氮-5-氧代-1-正亮氨酸（DON）每日全身给药方案，和局部每周注射更狭窄的色氨酸分解代谢IDO-Gal3融合蛋白。治疗显著减少在皮下植入的纤维素盘周围形成的FBR胶囊。MI混合物导致相当薄的FBR胶囊（对照的40％），而每周局部注射IDO-Gal3也导致较薄的FBR胶囊(对照的69%)。RNA测序胶囊转录显示MI鸡尾酒促进静止，随着抗原加工和呈递的减少，T辅助亚群分化，和细胞因子-细胞因子受体途径。IDO-Gal3促进促再生，选择性激活的M2样巨噬细胞和T辅助细胞2，与2型反应相关基因（Il4，Il13，Arg1，Mrc1，Chil3，Gata3）的表达增加。IDO-Gal3降低促炎先天感知途径，和C型凝集素受体，NOD样受体,RIG-I样受体,和Toll样受体信号。与对照FBR胶囊相比，这项工作有助于确定免疫代谢调节期间FBR胶囊中伴随调节的关键基因靶标和途径。
