Jesse Brown VA Medical Center and The University of Illinois at Chicago.
Midwestern University, Downers Grove, Illinois.
Arthritis Rheumatol. 2021 Nov;73(11):2003-2014. doi: 10.1002/art.41792. Epub 2021 Sep 22.
In rheumatoid arthritis (RA), elevated serum interleukin-34 (IL-34) levels are linked with increased disease severity. IL-34 binds to 2 receptors, macrophage colony-stimulating factor receptor (M-CSFR) and syndecan 1, which are coexpressed in RA macrophages. Expression of both IL-34 and syndecan 1 is strikingly elevated in the RA synovium, yet their mechanisms of action remain undefined. This study was undertaken to investigate the mechanism of action of IL-34 in RA.
To characterize the significance of IL-34 in immunometabolism, its mechanism of action was elucidated in joint macrophages, fibroblasts, and T effector cells using RA and preclinical models.
Intriguingly, syndecan 1 activated IL-34-induced M-CSFR phosphorylation and reprogrammed RA naive cells into distinctive CD14+CD86+GLUT1+ M34 macrophages that expressed elevated levels of IL-1β, CXCL8, and CCL2. In murine M34 macrophages, the inflammatory phenotype was accompanied by potentiated glycolytic activity, exhibited by transcriptional up-regulation of GLUT1, c-Myc, and hypoxia-inducible factor 1α (HIF-1α) and amplified pyruvate and l-lactate secretion. Local expression of IL-34 provoked arthritis by expanding the glycolytic F4/80-positive, inducible nitric oxide synthase (iNOS)-positive macrophage population, which in turn attracted fibroblasts and polarized Th1/Th17 cells. The cross-talk between murine M34 macrophages and Th1/Th17 cells broadened the inflammatory and metabolic phenotypes, resulting in the expansion of IL-34 pathogenicity. Consequently, IL-34-instigated joint inflammation was alleviated in RAG mice compared to wild-type mice. Syndecan 1 deficiency attenuated IL-34-induced arthritis by interfering with joint glycolytic M34 macrophage and osteoclast remodeling. Similarly, inhibition of glycolysis by 2-deoxy-d-glucose reversed the joint swelling and metabolic rewiring triggered by IL-34 via HIF-1α and c-Myc induction.
IL-34 is a novel endogenous factor that remodels hypermetabolic M34 macrophages and facilitates their cross-regulation with T effector cells to advance inflammatory bone destruction in RA.
在类风湿关节炎（RA）中，升高的血清白细胞介素 34（IL-34）水平与疾病严重程度增加有关。IL-34 与 2 种受体结合，即巨噬细胞集落刺激因子受体（M-CSFR）和 syndecan 1，这两种受体在 RA 巨噬细胞中共表达。RA 滑膜中 IL-34 和 syndecan 1 的表达均显著升高，但它们的作用机制尚不清楚。本研究旨在探讨 IL-34 在 RA 中的作用机制。
为了研究 IL-34 在免疫代谢中的意义，我们使用 RA 和临床前模型，在关节巨噬细胞、成纤维细胞和 T 效应细胞中阐明了其作用机制。
有趣的是，syndecan 1 激活了 IL-34 诱导的 M-CSFR 磷酸化，并将 RA 幼稚细胞重编程为独特的 CD14+CD86+GLUT1+M34 巨噬细胞，这些巨噬细胞表达高水平的 IL-1β、CXCL8 和 CCL2。在鼠 M34 巨噬细胞中，炎症表型伴随着增强的糖酵解活性，表现为 GLUT1、c-Myc 和缺氧诱导因子 1α（HIF-1α）的转录上调，以及丙酮酸和 l-乳酸的分泌增加。IL-34 的局部表达通过扩展糖酵解阳性、诱导型一氧化氮合酶（iNOS）阳性的 F4/80 阳性巨噬细胞群引起关节炎，进而吸引成纤维细胞和极化 Th1/Th17 细胞。鼠 M34 巨噬细胞与 Th1/Th17 细胞之间的相互作用扩大了炎症和代谢表型，导致 IL-34 致病性的扩大。因此，与野生型小鼠相比，RAG 小鼠中的 IL-34 诱导性关节炎减轻。syndecan 1 缺乏通过干扰关节糖酵解 M34 巨噬细胞和破骨细胞重塑来减轻 IL-34 诱导的关节炎。同样，通过 HIF-1α 和 c-Myc 诱导，2-脱氧-d-葡萄糖抑制糖酵解可逆转 IL-34 引发的关节肿胀和代谢重编程。
IL-34 是一种新型的内源性因子，可重塑代谢旺盛的 M34 巨噬细胞，并促进其与 T 效应细胞的交叉调节，从而促进 RA 中的炎症性骨破坏。
