Rheumatology Research and Advanced Therapeutics, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Ann Rheum Dis. 2013 Aug;72(8):1407-15. doi: 10.1136/annrheumdis-2012-202467. Epub 2013 Jan 3.
A prominent role of Toll-like receptor 4 (TLR4) in arthritis is emerging. TLR4 is functional in immune cells and stromal cells. The aim was to investigate the involvement of TLR4 in bone marrow (BM)-derived and resident cells in arthritis.
Reciprocal sex-mismatched BM transplantation was performed between IL-1Ra(-/-)TLR4(+/+) and IL-1Ra(-/-)TLR4(-/-) double knockout animals in Balb/c background. Arthritis was assessed macroscopically and by histopathology. Immunity was evaluated by splenic cytokine production and flow cytometry in draining lymph node (DLN) cells.
Arthritis progression was reduced to a similar extent in animals lacking TLR4 on BM-derived, resident cells or both. Histology revealed that joint inflammation was partially TLR4-dependent in either BM-derived or resident cells. TLR4 plays an additive role in BM-derived and resident cells in promoting cartilage erosion. By contrast, TLR4 was equally important in BM-derived and resident cells in mediating bone erosion. Systemically, TLR4 in both BM-derived and resident cells contributed to IL-17 production by splenic T-cells, whereas in the DLNs of arthritic joints this was not the case. Interestingly, in DLN, the dominant cells producing IL-17 were CD4 negative, and cell numbers were determined by TLR4 in the BM-derived cells.
TLR4 is necessary in both BM-derived and resident cells for full-blown joint swelling, inflammation and bone erosion. Furthermore, TLR4 on BM-derived and tissue-resident cells show an additive effect in cartilage destruction. Interestingly, TLR4 on BM-derived and tissue-resident cells are both required for IL-17 production in spleen, but only in BM-derived cells in DLN.
Toll 样受体 4（TLR4）在关节炎中起着重要作用。TLR4 在免疫细胞和基质细胞中发挥功能。本研究旨在探讨 TLR4 在骨髓（BM）来源细胞和固有细胞中在关节炎中的作用。
在 Balb/c 背景下，将 IL-1Ra（-/-）TLR4（+/+）和 IL-1Ra（-/-）TLR4（-/-）双基因敲除小鼠进行雌雄配对的 BM 移植。通过宏观和组织病理学评估关节炎。通过脾细胞细胞因子产生和引流淋巴结（DLN）细胞的流式细胞术评估免疫。
在缺乏 TLR4 的 BM 来源、固有细胞或两者均缺乏的动物中，关节炎的进展程度相似地减少。组织学显示，关节炎症在 BM 来源或固有细胞中至少部分依赖于 TLR4。TLR4 在促进软骨侵蚀中在 BM 来源细胞和固有细胞中发挥相加作用。相比之下，TLR4 在 BM 来源细胞和固有细胞中在介导骨侵蚀方面同样重要。在系统中，TLR4 在 BM 来源细胞和固有细胞中均有助于脾 T 细胞产生 IL-17，而在关节炎关节的 DLN 中则不然。有趣的是，在 DLN 中，产生 IL-17 的主要细胞是 CD4 阴性细胞，细胞数量由 BM 来源细胞中的 TLR4 决定。
TLR4 在完全性关节肿胀、炎症和骨侵蚀中在 BM 来源细胞和固有细胞中都是必需的。此外，TLR4 在 BM 来源细胞和组织固有细胞中在软骨破坏中具有相加作用。有趣的是，TLR4 在 BM 来源细胞和组织固有细胞中都需要在脾脏中产生 IL-17，但仅在 DLN 中的 BM 来源细胞中需要。
