Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 15 rue de l'Ecole de Médicine, F-75006, Paris, France.
CSL Behring, Research, CSL Biologics Research Center, 3014, Bern, Switzerland.
Commun Biol. 2020 Mar 4;3(1):96. doi: 10.1038/s42003-020-0825-4.
Therapeutic normal IgG intravenous immunoglobulin (IVIG) is a well-established first-line immunotherapy for many autoimmune and inflammatory diseases. Though several mechanisms have been proposed for the anti-inflammatory actions of IVIG, associated signaling pathways are not well studied. As β-catenin, the central component of the canonical Wnt pathway, plays an important role in imparting tolerogenic properties to dendritic cells (DCs) and in reducing inflammation, we explored whether IVIG induces the β-catenin pathway to exert anti-inflammatory effects. We show that IVIG in an IgG-sialylation independent manner activates β-catenin in human DCs along with upregulation of Wnt5a secretion. Mechanistically, β-catenin activation by IVIG requires intact IgG and LRP5/6 co-receptors, but FcγRIIA and Syk are not implicated. Despite induction of β-catenin, this pathway is dispensable for anti-inflammatory actions of IVIG in vitro and for mediating the protection against experimental autoimmune encephalomyelitis in vivo in mice, and reciprocal regulation of effector Th17/Th1 and regulatory T cells.
治疗性正常 IgG 静脉注射免疫球蛋白 (IVIG) 是许多自身免疫性和炎症性疾病的成熟一线免疫疗法。尽管已经提出了 IVIG 抗炎作用的几种机制，但相关信号通路尚未得到很好的研究。由于 β-连环蛋白是经典 Wnt 途径的核心组成部分，在赋予树突状细胞 (DC) 耐受特性和减少炎症方面发挥着重要作用，我们探讨了 IVIG 是否诱导 β-连环蛋白途径发挥抗炎作用。我们表明，IVIG 以 IgG 唾液酸化非依赖性方式激活人 DC 中的 β-连环蛋白，同时上调 Wnt5a 的分泌。从机制上讲，IVIG 通过β-连环蛋白的激活需要完整的 IgG 和 LRP5/6 共受体，但不涉及 FcγRIIA 和 Syk。尽管诱导了β-连环蛋白，但该途径对于 IVIG 的体外抗炎作用以及在体内介导对实验性自身免疫性脑脊髓炎的保护作用是可有可无的，并且对效应性 Th17/Th1 和调节性 T 细胞具有反向调节作用。
