Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Distinct macrophage polarization in acute and chronic gout


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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Data availability

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


  1. Dalbeth N, Gosling AL, Gaffo A, Abhishek A. Gout. Lancet 397, 1843–1855 (2021).

  2. Martin WJ, Walton M, Harper J. Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute gout. Arthritis Rheum 60, 281–289 (2009).

  3. Funes SC, Rios M, Escobar-Vera J, Kalergis AM. Implications of macrophage polarization in autoimmunity. Immunology 154, 186–195 (2018).

  4. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8, 958–969 (2008).

  5. Mills CD. M1 and M2 macrophages: oracles of health and disease. Crit Rev Immunol 32, 463–488 (2012).

  6. Orecchioni M, Ghosheh Y, Pramod AB, Ley K. Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages. Front Immunol 10, 1084 (2019).

  7. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

  8. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122, 787–795 (2012).

  9. Cavalli G, Dinarello CA. Suppression of inflammation and acquired immunity by IL-37. Immunol Rev 281, 179–190 (2018).

  10. Liu L, Xue Y, Zhu Y, Xuan D, Yang X, Liang M, et al. Interleukin 37 limits monosodium urate crystal-induced innate immune responses in human and murine models of gout. Arthritis Res Ther 18, 268 (2016).

  11. Denko CW, Whitehouse MW. Experimental inflammation induced by naturally occurring microcrystalline calcium salts. J Rheumatol 3, 54–62 (1976).

  12. Post AM, Katsikis PD, Tait JF, Geaghan SM, Strauss HW, Blankenberg FG. Imaging cell death with radiolabeled annexin V in an experimental model of rheumatoid arthritis. J Nucl Med 43, 1359–1365 (2002)..

  13. Németh T, Sperandio M, Mócsai A. Neutrophils as emerging therapeutic targets. Nat Rev Drug Discov 19, 253–275 (2020).

  14. Schauer C, Janko C, Munoz LE, Zhao Y, Kienhöfer D, Frey B, et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat Med 20, 511–517 (2014).

  15. Rose DM, Sydlaske AD, Agha-Babakhani A, Johnson K, Terkeltaub R. Transglutaminase 2 limits murine peritoneal acute gout-like inflammation by regulating macrophage clearance of apoptotic neutrophils. Arthritis Rheum 54, 3363–3371 (2006).

  16. Amaral FA, Costa VV, Tavares LD, Sachs D, Coelho FM, Fagundes CT, et al. NLRP3 inflammasome-mediated neutrophil recruitment and hypernociception depend on leukotriene B (4) in a murine model of gout. Arthritis Rheum 64, 474–484 (2012).

  17. Oliviero F, Scanu A. How Factors Involved in the Resolution of Crystal-Induced Inflammation Target IL-1β. Front Pharmacol 8, 164 (2017).

  18. Landis RC, Yagnik DR, Florey O, Philippidis P, Emons V, Mason JC, et al. Safe disposal of inflammatory monosodium urate monohydrate crystals by differentiated macrophages. Arthritis Rheum 46, 3026–3033 (2002).

  19. Chen CJ, Shi Y, Hearn A, Fitzgerald K, Golenbock D, Reed G, et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J Clin Invest 116, 2262–2271 (2006).

  20. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

  21. Murakami Y, Akahoshi T, Hayashi I, Endo H, Kawai S, Inoue M, et al. Induction of triggering receptor expressed on myeloid cells 1 in murine resident peritoneal macrophages by monosodium urate monohydrate crystals. Arthritis Rheum 54, 455–462 (2006).

  22. Martin WJ, Shaw O, Liu X, Steiger S, Harper JL. Monosodium urate monohydrate crystal-recruited noninflammatory monocytes differentiate into M1-like proinflammatory macrophages in a peritoneal murine model of gout. Arthritis Rheum 63, 1322–1332 (2011).

  23. Locati M, Curtale G, Mantovani A. Diversity, Mechanisms, and Significance of Macrophage Plasticity. Annu Rev Pathol 15, 123–147 (2020).

  24. Zhang B, Xu H, Chen J, Zhu X, Xue Y, Yang Y, et al. Highly specific and label-free histological identification of microcrystals in fresh human gout tissues with stimulated Raman scattering. Theranostics 11, 3074–3088 (2021).

  25. Zhao L, Zhao T, Yang X, Cao L, Xu R, Liu J, et al. IL-37 blocks gouty inflammation by shaping macrophages into a non-inflammatory phagocytic phenotype. Rheumatology keac009 (2022).

Download references


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

Author information

Authors and Affiliations



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.

Corresponding authors

Correspondence to Lei Liu or Yu Xue.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhao, L., Ye, W., Zhu, Y. et al. Distinct macrophage polarization in acute and chronic gout. Lab Invest (2022).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links