Lukač Nina, Flegar Darja, Priselac Sara, Kelava Tomislav, Šućur Alan, Filipović Maša, Šisl Dino, Fadljević Martina, Radanović Igor, Katavić Vedran, Zimmermann Nives, Grčević Danka, Kovačić Nataša
Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia.
Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia.
Front Cell Dev Biol. 2025 May 15;13:1451093. doi: 10.3389/fcell.2025.1451093. eCollection 2025.
Rheumatoid arthritis is the most common immune-mediated joint disease, whose pathogenesis includes both innate and acquired immune mechanisms. Fas/Fas ligand system is considered to have a dual role in arthritis, inducing apoptotic cell death of hyperplastic synoviocytes and inflammatory cells, but also exerts proinflammatory effects. In our study, absence of Fas resulted in decreased accumulation of myeloid cells in affected joints.
Proportions of synovial hematopoietic cells were assessed by flow cytometry in wild-type and mice with antigen-induced arthritis. Effects of myeloid-specific ablation of Fas on the course of antigen-induced arthritis was assessed using Fas/LysMCre model. Arthritis was scored visually, histologically and by micro-computerized tomography. Transcriptome of sorted CD11bGr-1 cells was analyzed by microarray, and effects of potential molecular driver Midline-1 (Mid-1) were analyzed and using mice.
Ameliorated antigen-induced arthritis in mice is characterized by the lack of synovial accumulation of myeloid CD11bGr-1 cells. However, myeloid-specific ablation of Fas was not sufficient to ameliorate arthritis, suggesting proinflammatory effects of Fas in multiple cell subsets in arthritis. Myeloid cells from mice downregulated limited number of genes including . Stimulation of bone marrow cells with low doses of soluble Fas agonist upregulated expression of . Inactivation of had a variable anti-inflammatory effects and partial anti-arthritic effect .
Functional Fas is required for the recruitment and accumulation of innate inflammatory cells in arthritic joints. This accumulation is not driven exclusively by mediators expressed in accumulated subset. enhances inflammatory polarization of myeloid cells and promotes bone and cartilage degradation in arthritis.
类风湿性关节炎是最常见的免疫介导性关节疾病，其发病机制包括先天性和获得性免疫机制。Fas/Fas配体系统在关节炎中被认为具有双重作用，既能诱导增生性滑膜细胞和炎性细胞发生凋亡性细胞死亡，又能发挥促炎作用。在我们的研究中，Fas缺失导致受影响关节中髓样细胞的积聚减少。
通过流式细胞术评估野生型和抗原诱导性关节炎小鼠滑膜造血细胞的比例。使用Fas/LysMCre模型评估Fas在髓样细胞中的特异性缺失对抗原诱导性关节炎病程的影响。通过视觉、组织学和微型计算机断层扫描对关节炎进行评分。通过微阵列分析分选的CD11bGr-1细胞的转录组，并使用小鼠分析潜在分子驱动因子中线-1（Mid-1）的作用。
Fas基因敲除小鼠中抗原诱导性关节炎的改善表现为髓样CD11bGr-1细胞在滑膜中缺乏积聚。然而，Fas在髓样细胞中的特异性缺失不足以改善关节炎，这表明Fas在关节炎的多个细胞亚群中具有促炎作用。Fas基因敲除小鼠的髓样细胞下调了包括……在内的有限数量的基因。用低剂量可溶性Fas激动剂刺激骨髓细胞可上调……的表达。Mid-1的失活具有可变的抗炎作用和部分抗关节炎作用。
功能性Fas是关节炎关节中先天性炎性细胞募集和积聚所必需的。这种积聚并非仅由积聚亚群中表达的介质驱动。Mid-1增强了髓样细胞的炎性极化，并促进了关节炎中骨和软骨的降解。
