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Distinct macrophage polarization in acute and chronic gout

Abstract

Macrophage polarization mediates the development of inflammatory diseases. However, the polarization status at various stages of gout is not fully understood. Our study aimed to define the evolution of macrophage polarization in acute and chronic gout. Normal human synovium and synovium with tophi were collected for immunofluorescence (IF). Rat gouty joints were collected for joint thickness assessment and pathological evaluation. Tissue mRNA expression of inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1) were evaluated. Mouse peritoneal macrophages and THP-1 derived macrophages were stimulated by monosodium urate (MSU) crystals and were collected for detection of interleukin (IL) -1β and IL-37 levels and iNOS/Arg-1 ratio. Arg-1 and IL-37 were highly expressed in normal synovium and synovium with tophi. In rat gouty joints, the inflammatory cell counts and ankle thickness began to increase at 2 h, peaked at 24 h, and was decreased spontaneously. An increase in macrophages preceded the neutrophils infiltration. Infiltration of M1 was positively related with the severity of arthritis. M2 appeared in an early stage (at 2 h) of inflammation. The number of M1 macrophages was comparable to that of M2 from 2 to 12 h and exceeded M2 number at 18 h and 24 h. The ratios of M2/M1 reversed at 48 h and remained reversed until 120 h. In mice gouty joints, iNOS/Arg-1 mRNA ratio was significantly higher than the that in control group at 8 h. The proportion of neutrophils and M1-macrophages reached peak at 4 h in mice model with peritoneal gout. Concentration of IL-1β and ratio of iNOS/Arg-1 were increased at 6 h, peaked at 48 h, and were then decreased at 72 h in vitro, while the concentration of IL-37 peaked at 2 h and then decreased. In summary, altered macrophage polarization was observed in various stages of gouty inflammation. Macrophages in acute gout were polarized into M1 at early stage and into M2 at later stage while the macrophages in chronic gout mainly were only polarized towards M2. The number of M1 rose with the progression of inflammation. Early increase of M2 was observed, which might be generated directly from M0.

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Fig. 1: The expression of CD14, iNOS and Arg-1 in normal synovium and synovium with tophi.
Fig. 2: The expression of CD14, IL-1β and IL-37 in normal synovium and synovium with tophi.
Fig. 3: MSU-induced gouty arthritis in Wistar rat.
Fig. 4: The polarization of macrophages in rat gouty arthritis.
Fig. 5: MSU-induced gouty peritonitis in mice.
Fig. 6: MSU-induced gouty arthritis in mice.
Fig. 7: THP-1 derived macrophages induced by MSU.

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The data underlying this article will be shared on reasonable request to the corresponding author.

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Funding

This work was supported by National Natural Science Foundation of China (82071756) and the Research Funding from the Shanghai Hospital Development Center (SHDC2020CR1013).

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LZ carried out the mouse studies and cells studies and participated in the manuscript drafting. WJY performed the statistical analysis and participated in the manuscript drafting. YFZ and ZGD were responsible for the pathological assessment. FFC, XXL and QW performed the statistical analysis. YHH provided pathological specimens. XXZ and YYY helped to revise the manuscript. HJZ, LL and YX conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lei Liu or Yu Xue.

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The authors declare no competing interests.

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All procedures on animals followed guidelines established by the Institutional Animal Care Committee and the China Council on Animal Care at Fudan University (Shanghai, China). The collection of human samples was approved by Ethics Committee of Huashan Hospital. All human samples were obtained with the patient’s written informed consent which was approved by Ethics Committee of Huashan Hospital.

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Zhao, L., Ye, W., Zhu, Y. et al. Distinct macrophage polarization in acute and chronic gout. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00798-4

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  • DOI: https://doi.org/10.1038/s41374-022-00798-4

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