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The Role of Interferon Regulatory Factor 5 in Macrophage Inflammation During Osteoarthritis

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Abstract

Mounting evidence suggests that aberrant immune responses are involved in the pathogenesis of osteoarthritis (OA). Synovial macrophages are likely involved. In this study, we sought to investigate the role of interferon regulatory factor 5 (IRF5). In vitro M1-polarized macrophages presented significantly higher IRF5 expression than M2-polarized macrophages. Interestingly, IRF5 expression was observed in macrophages from the synovial fluid of OA patients, and the level of IRF expression was positively correlated with disease severity, such that stage 4 OA synovial macrophages presented significantly higher levels of IRF5 than stage 2 and stage 3 OA synovial macrophages. Circulating monocytes from OA patients, on the other hand, expressed little IRF5. However, synovial fluid from OA patients could significantly upregulate IRF5 expression in circulating monocytes. Synovial macrophages also expressed significantly higher IL-12 than circulating monocytes, and circulating monocytes conditioned in OA synovial fluid demonstrated significantly higher IL-12 expression. Direct IRF5 transfection could increase IL-12 expression in circulating monocytes. Interestingly, IRF5-transfected monocytes promoted the expression of Th1-associated genes in naive CD4 T cells via an IL-12-dependent mechanism. Overall, our study demonstrated that IRF5 expression was associated with OA severity and could contribute to the activation of the M1-Th1 axis.

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Author notes

  1. Zhiming Ni and Xinhua Zhao contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics, 903 Hospital of PLA, 136 Tiancheng Road, Hangzhou, 310013, Zhejiang, China

    Zhiming Ni, Xinhua Zhao, Xingqin Dai, Lu Zhao & Junjie Xia

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  1. Zhiming Ni
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Correspondence to Junjie Xia.

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Supplementary Figure 1

Isolation of monocytes and differentiation of M1 and M2 macrophages. (A) Expression of monocyte marker CD14 before and after magnetic negative enrichment of monocytes. One representative healthy participant is shown. (B) Expression of M1 marker NOS2 and M2 marker ARG1 in M1- and M2-polarized macrophages, respectively. Student’s t test. ***p < 0.001. (PNG 194 kb)

High Resolution Image (TIFF 270 kb)

Supplementary Figure 2

The frequency of naive CD4 T (CD3+CD4+CD45RA+) cells before and after magnetic negative enrichment. Figures shown were pre-gated on live lymphocytes. One representative healthy participant is shown. (PNG 291 kb)

High Resolution Image (TIFF 382 kb)

Supplementary Figure 3

The expression of IFN-γ mRNA by CD4 T cells in the coculture with monocytes at various time points. Naive CD4 T cells were isolated via magnetic negative selection, and then co-incubated with autologous mock-transfected or IRF5-transfected circulating monocytes at 1/1 ratio. The CD4 T cells were harvested at various time points and the expression of IFN-γ-mRNA was examined. Experiment was performed in one stage 2 (Subject 1), one stage 3 (Subject 2), and one stage 4 (Subject 3) patients. (PNG 70 kb)

High Resolution Image (TIFF 101 kb)

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Ni, Z., Zhao, X., Dai, X. et al. The Role of Interferon Regulatory Factor 5 in Macrophage Inflammation During Osteoarthritis. Inflammation 42, 1821–1829 (2019). https://doi.org/10.1007/s10753-019-01044-8

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  • DOI: https://doi.org/10.1007/s10753-019-01044-8

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