Regenerative Processing Plant, LLC, Palm Harbor, Florida.
Faculty of Medical Sciences, Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, University of Kragujevac, Kragujevac, Serbia.
Biofactors. 2020 Mar;46(2):263-275. doi: 10.1002/biof.1587. Epub 2019 Nov 22.
Interleukin (IL)-1 receptor antagonist (IL-1Ra), a naturally occurring antagonist of IL-1α/IL-1β signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells (MSCs). MSCs, in IL-1Ra-dependent manner, suppressed production of IL-1β in dermal macrophages, induced their polarization in anti-inflammatory M2 phenotype, attenuated antigen-presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL-1β in macrophages were mainly responsible for beneficial effects of MSC-derived IL-1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL-1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL-1Ra-dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL-1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC-treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL-1Ra-dependent inhibition of IL-1α/IL-1β-signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC-derived IL-1Ra before IL-1Ra-overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.
白细胞介素 (IL)-1 受体拮抗剂 (IL-1Ra) 是 IL-1α/IL-1β 信号通路的天然拮抗剂，它被认为是间充质干细胞 (MSCs) 免疫抑制作用的原因。MSCs 以依赖于 IL-1Ra 的方式抑制真皮巨噬细胞中 IL-1β 的产生，诱导其向抗炎 M2 表型极化，减弱树突状细胞 (DCs) 的抗原呈递特性，并促进皮肤中免疫抑制性 T 调节细胞的扩增，从而增强非愈合性伤口的修复。巨噬细胞中炎症小体的活性降低和 IL-1β 的产生受到抑制，主要是 MSC 衍生的 IL-1Ra 在减轻急性肺损伤、干眼症和角膜损伤方面有益作用的原因。通过产生 IL-1Ra，MSCs 减少了 DC 向引流淋巴结的迁移，并减弱了炎症性 Th1 和 Th17 细胞的生成，从而减轻暴发性肝炎和类风湿性关节炎。MSCs 以依赖于 IL-1Ra 的方式抑制肝星状细胞产生 I 型胶原，从而减少肝纤维化。IL-1Ra 至少部分负责增强 MSC 处理的部分肝切除和骨关节炎动物中肝细胞和软骨细胞的增殖。尽管有这些有益的作用，但 IL-1Ra 依赖性抑制 IL-1α/IL-1β 信号显著增加了感染的风险。因此，未来的实验和临床研究应该在将 IL-1Ra 过表达的 MSC 用作治疗急性和慢性炎症性疾病的潜在新治疗剂之前，阐明 MSC 衍生的 IL-1Ra 的潜在副作用。
