Abstract
ObjectivesBone marrow edema is a universal manifestation of rheumatoid arthritis (RA), and its pathological essence is a bone marrow lesion (BML) formed by various bone marrow (BM) immune cells. Neutrophils play an important role in inflammatory arthritis, but the role and mechanism of neutrophils in BML are not clear.Materials and methodsGranulocyte colony‐stimulating factor (G‐CSF) −/− mice and wild type (WT) C57BL/6 mice were immunized for collagen‐induced arthritis (CIA). Histological scores of arthritis were evaluated. Immunohistochemistry staining with anti‐Ly6G was conducted. Neutrophil extracellular traps (NETs) in joint sections were determined by immunofluorescence staining. BM neutrophils were isolated for flow cytometry and NETosis induction in vitro.ResultsHistological study showed significant neutrophil infiltrations in BML of CIA mice. Inhibition of BM neutrophil production by G‐CSF knock out can obstruct the induction of BML and CIA. In addition to abundant infiltrated NETs intra‐articular, remarkable NETosis primed BM neutrophils were infiltrated in BML of CIA mice, which was positively related to bone erosion. Neutrophils derived from G‐CSF−/− mice have diminished ability of NETs formation in vitro, while G‐CSF induction can enhance its capacity of NETs formation.ConclusionsWe propose for the first time that the overproduced BM neutrophils in CIA mice are primed for NETosis in a G‐CSF dependent manner, and these pathogenic cells may have an important role in inflammatory arthritis. Blocking this pathological process could be a potential strategy for the treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a complex autoimmune disease involving immune cells, synovial cells, osteoclasts, and other cells
With Granulocyte colony-stimulating factor (G-CSF) induction, bone marrow (BM) neutrophils from both wild type (WT) and G-CSF−/− mice showed enhanced NETosis (Figure 7A,B). These results show that neutrophils derived from BM lacking G-CSF have diminished ability of Neutrophil extracellular traps (NETs) formation in vitro, and G-CSF induction can enhance its capacity of NETs formation.G-CSF has a role in NETosis of BM neutrophils
Whether neutrophils participate in bone marrow lesion (BML) of RA has not been reported
Summary
Rheumatoid arthritis (RA) is a complex autoimmune disease involving immune cells, synovial cells, osteoclasts, and other cells. T, B lymphocytes, dendritic cells, macrophages, and other immune cells play an important role in the occurrence and development of RA, but the exact pathogenesis of RA is still unclear.[1] The majority of researchers have focused on lesions in the synovium, cartilage, and bone cortex, but immune cells in the subchondral bone marrow (BM) play a role in RA.[2]. From a pathological point of view, the essence of BME is that normal adipose tissue is replaced by inflammatory cells mainly composed of T, B lymphocytes.[7,8] This pathological manifestation is called bone marrow lesions (BMLs).[9] McQueen et al proposed the pathogenesis hypothesis of BML in RA, suggesting that pathological cells migrate from subchondral bone to synovium to play a role.[10] there are few studies in this field, and the exact role and mechanism of BML in RA is still unclear. Histological score of arthritis was evaluated by two investigators separately who were blinded to grouping information, according to a previously described scoring system on the extent of synovitis, pannus formation, bone and/or cartilageerosion, as following criteria: 0: no signs of inflammation; 1: mild inflammation with hyperplasia of the synovial lining layer, minimal without cartilageerosion; 2 to 4: increasing degrees of inflammatory cell infiltrate, or cartilage and bone erosion.[15]
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