The Immune Cell Landscape in Different Anatomical Structures of Knee in Osteoarthritis: A Gene Expression-Based Study

Abstract

Background. Immunological mechanisms play a vital role in the pathogenesis of knee osteoarthritis (KOA). Moreover, the immune phenotype is a relevant prognostic factor in various immune-related diseases. In this study, we used CIBERSORT for deconvolution of global gene expression data to define the immune cell landscape of different structures of knee in osteoarthritis. Methods and Findings. By applying CIBERSORT, we assessed the relative proportions of immune cells in 76 samples of knee cartilage, 146 samples of knee synovial tissue, 40 samples of meniscus, and 50 samples of knee subchondral bone. Enumeration and activation status of 22 immune cell subtypes were provided by the obtained immune cell profiles. In synovial tissues, the differences in proportions of plasma cells, M1 macrophages, M2 macrophages, activated dendritic cells, resting mast cells, and eosinophils between normal tissues and osteoarthritic tissues were statistically significant (P<0.05). The area under the curve was relatively large in resting mast cells, dendritic cells, and M2 macrophages in receiver operating characteristic analyses. In subchondral bones, the differences in proportions of resting master cells and neutrophils between normal tissues and osteoarthritic tissues were statistically significant (P<0.05). In subchondral bones, the proportions of immune cells, from the principle component analyses, displayed distinct group-bias clustering. Resting mast cells and T cell CD8 were the major component of first component. Moreover, we revealed the potential interaction between immune cells. There was almost no infiltration of immune cells in the meniscus and cartilage of the knee joint. Conclusions. The immune cell composition in KOA differed substantially from that of healthy joint tissue, while it also differed in different anatomical structures of the knee. Meanwhile, activated mast cells were mainly associated with high immune cell infiltration in OA. Furthermore, we speculate M2 macrophages in synovium and mast cells in subchondral bone may play an important role in the pathogenesis of OA.

The inflammatory speech of fibroblasts

“…The fibrotic OA synovium contains a larger number of inflammatory M1-like macrophages compared to normal synovium, which express cell surface markers HLADR, CD63, and CD86. 213,236,241,242 The fibrotic synovium also contains a greater number of tissue repair M2-like macrophages compared to normal tissue, 236 consistent with large populations of NUPR1+ macrophages found in OA compared to inflammatory RA synovium. 238 These findings suggest that both M1-and M2-like macrophage populations contribute to OA synovial fibrosis.…”

“…OA synovium is heterogeneous with respect to the involvement of fibrosis but synovial hyperplasia, cell proliferation, increased collagen deposition, multiple inflammatory cell infiltrates, and presence of sensory neurons are common. [234][235][236][237] Most cells associated with OA synovium are FLS and endothelial cells, with macrophages and T-cells making up most of the remaining cell types 238 (Figure 4). Recent evidence suggests that fibrosis is inversely correlated with inflammation and severity of OA and thus may represent a protective mechanism if established early.…”

“…Compared to peripheral blood, T-cells isolated from the synovial membrane and activated in vitro release significantly more IL-6 and IL-10, but also express modest levels of TNFα and IL-2, consistent with activated CD4 + and Treg populations found in the membrane. 236,245 Thus, macrophages and T-cells represent important immune cell F I G U R E 5 Comparison of macrophage and fibroblast-like synoviocyte (FLS) interactions and contributions in RA versus OA. In RA, most macrophages are M1-like while in OA, M2-like macrophages prevail; however, both macrophage types are present in both OA and RA synovium.…”

Communications Between Bone Marrow Macrophages and Bone Cells in Bone Remodeling

“…The high proportion of M2 macrophages in the synovial tissues has certain clinical diagnostic significance for OA (Chen et al, 2020 ), and the pro-inflammatory M1 macrophages are also increased significantly (Sun et al, 2017 ). Some studies have confirmed that macrophages play an important role in the occurrence of OA through inflammatory factors, cytokines and proteins, whether it is inflammatory or mechanical injury (Bondeson et al, 2010 ).…”

Bone marrow derived mast cells injected into the osteoarthritic knee joints of mice induced by sodium monoiodoacetate enhanced spontaneous pain through activation of PAR2 and action of extracellular ATP

“…Pain development in OA has been shown to be well correlated with bone marrow lesion [ 1 , 45 , 46 ]. In osteoarthritic subchondral bones, the most abundant infiltrating immune cells were shown to be T cell CD8, activated mast cells and activated T cell CD4 memory, while in normal synovial samples, the most abundant infiltrating immune cells were resting mast cells, monocytes, and neutrophils [ 47 ]. BMMCs injected into the OA knee joints may function in a similar manner to the abundant activated mast cells present in the bone marrow lesion.…”