Overproduced bone marrow neutrophils in collagen‐induced arthritis are primed for NETosis: An ignored pathological cell involving inflammatory arthritis

OBJECTIVES: Bone 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 METHODS: Granulocyte 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. RESULTS: Histological 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. CONCLUSIONS: We 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.