Evidence for M2 macrophage activation in patients with enthesitis-related arthritis category of juvenile idiopathic arthritis

  • Shruti Bhattacharya
  • Akhilesh Yadav
  • Amita AggarwalEmail author
Brief Report


Recently, an increase in CD163+ macrophages in ileal biopsies from ankylosing spondylitis patients and an increase in intermediate monocytes in enthesitis-related arthritis (ERA) have been reported. Thus, we studied sCD163 levels as M2 macrophage marker in serum and synovial fluid (SF) of ERA children and CD163 expression on monocyte subsets. Serum samples from ERA patients and healthy controls (HC) were assayed for sCD163 (ELISA). Serum and SF from ERA patients were analyzed when available from same patient (paired samples). In 10 patients, the CD163 expression level was analyzed on monocyte subsets by flow cytometry. Results are expressed as median (interquartile range (IQR)). Sera from 85 patients, SF from 32 ERA patients, and serum from 46 HC were analyzed. The average age at inclusion was 16 ± 3.24 years and age at onset was 11.2 ± 2.79 years. Seventy-nine of them were boys and HLA-B27 was positive in 64/80 patients. The median serum sCD163 levels were higher in patients [1080 (1305.2) ng/ml] than HC [780 (812.5) ng/ml; p < 0.001]. The SF levels [9000 (1250) ng/ml] were much higher than serum [3800 (3287.66) ng/ml; p < 0.001]. Disease activity data was available in 56 patients. Mean tender joint count was 2 (3), swollen joint count was 2 (2), ESR was 70 (65) mm and CRP was 7.1 (8.9) mg/dl. Serum sCD163 levels correlated with SF but not with disease activity. Intermediate monocytes (CD14+CD16+) from ERA patients had higher CD163 expression than HC. Elevated sCD163 levels in ERA patient’s sera and even higher levels in paired SF suggest towards activation of alternatively activated macrophages in ERA. Lack of correlation with activity may suggest that they have an immune-regulatory role in ERA.


Alternatively activated macrophages Innate immune system Juvenile spondyloarthropathy 



We thank all the residents of our department for their help in the collection of patient samples.


This work was supported by a grant from the Department of Science and Technology to AA (grant no. EMR/2015/000834). SB was supported by Senior Research Fellowship grant from Department of Biotechnology, New Delhi.

Compliance with ethical standards

Written informed consent was taken from all subjects. The study was approved by the institutional ethics committee (EMR/2015/000834).



Supplementary material

10067_2018_4408_MOESM1_ESM.docx (160 kb)
ESM 1 (DOCX 160 kb)


  1. 1.
    Ranganathan V, Gracey E, Brown MA, Inman RD, Haroon N (2017) Pathogenesis of ankylosing spondylitis - recent advances and future directions. Nat Rev Rheumatol 13:359–367CrossRefGoogle Scholar
  2. 2.
    Shikhagaie MM, Germar K, Bal SM, Ros XR, Spits H (2017) Innate lymphoid cells in autoimmunity: emerging regulators in rheumatic diseases. Nat Rev Rheumatol 13:164–173CrossRefGoogle Scholar
  3. 3.
    Conrad K, Wu P, Sieper J, Syrbe U (2015) In vivo pre-activation of monocytes in patients with axial spondyloarthritis. Arthritis Res Ther 17:179CrossRefGoogle Scholar
  4. 4.
    Buechler C, Ritter M, Orso E, Langmann T, Klucken J, Schmitz G (2000) Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol 67:97–103CrossRefGoogle Scholar
  5. 5.
    Etzerodt A, Moestrup SK (2013) CD163 and inflammation: biological, diagnostic, and therapeutic aspects. Antioxid Redox Signal 18:2352–2363CrossRefGoogle Scholar
  6. 6.
    Sulahian TH, Hogger P, Wahner AE Wardwell K, Goulding NJ, Sorg C, Droste A, Stehling M, Wallace PK, Morganelli PM, Guyre PM (2000) Human monocytes express CD163, which is upregulated by IL-10 and identical to p155. Cytokine 12:1312–1321CrossRefGoogle Scholar
  7. 7.
    Fabriek BO, van Bruggen R, Deng DM Ligtenberg AJ, Nazmi K, Schornagel K, Vloet RP, Dijkstra CD, van den Berg TK (2009) The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria. Blood 113:887–892CrossRefGoogle Scholar
  8. 8.
    Ciccia F, Alessandro R, Rizzo A, Accardo-Palumbo A, Raimondo S, Raiata F, Guggino G, Giardina A, De Leo G, Sireci G, Triolo G (2014) Macrophage phenotype in the subclinical gut inflammation of patients with ankylosing spondylitis. Rheumatology (Oxford) 53:104–113CrossRefGoogle Scholar
  9. 9.
    Moller HJ (2012) Soluble CD163. Scand J Clin Lab Invest 72:1–13CrossRefGoogle Scholar
  10. 10.
    Baeten D, Demetter P, Cuvelier CA Kruithof E, Van Damme N, De Vos M, Veys EM, De Keyser F (2002) Macrophages expressing the scavenger receptor CD163: a link between immune alterations of the gut and synovial inflammation in spondyloarthropathy. J Pathol 196:343–350CrossRefGoogle Scholar
  11. 11.
    Gaur P, Myles A, Misra R, Aggarwal A (2017) Intermediate monocytes are increased in enthesitis-related arthritis, a category of juvenile idiopathic arthritis. Clin Exp Immunol 187:234–241CrossRefGoogle Scholar
  12. 12.
    Zhao J, Yuan W, Tao C, Sun P, Yang Z, Xu W (2017) M2 polarization of monocytes in ankylosing spondylitis and relationship with inflammation and structural damage. APMIS 125:1070–1075CrossRefGoogle Scholar
  13. 13.
    Vandooren B, Noordenbos T, Ambarus C, Krausz S, Cantaert T, Yeremenko N, Boumans M, Lutter R, Tak PP, Baeten D (2009) Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis. Arthritis Rheum 60:966–975CrossRefGoogle Scholar
  14. 14.
    Tošovský M, Bradna P, Andrýs C, Andrýsova K, Čermáková E, Soukup T, Kubínová K, Krejsek J (2014) AB0166 the levels of soluble CD163 in patients with ankylosing spondylitis. Ann Rheum Dis 73:857–858Google Scholar
  15. 15.
    Hintz KA, Rassias AJ, Wardwell K, Moss ML, Morganelli PM, Pioli PA, Givan AL, Wallace PK, Yeager MP, Guyre PM (2002) Endotoxin induces rapid metalloproteinase-mediated shedding followed by up-regulation of the monocyte hemoglobin scavenger receptor CD163. J Leukoc Biol 72:711–717Google Scholar
  16. 16.
    Matsushita N, Kashiwagi M, Wait R, Nagayoshi R, Nakamura M, Matsuda T, Hogger P, Guyre PM, Nagase H, Matsuyama T (2002) Elevated levels of soluble CD163 in sera and fluids from rheumatoid arthritis patients and inhibition of the shedding of CD163 by TIMP-3. Clin Exp Immunol 130(1):156–161CrossRefGoogle Scholar
  17. 17.
    Baeten D, Moller HJ, Delanghe J, Veys EM, Moestrup SK, De Keyser F (2004) Association of CD163+ macrophages and local production of soluble CD163 with decreased lymphocyte activation in spondylarthropathy synovitis. Arthritis Rheum 50:1611–1623CrossRefGoogle Scholar
  18. 18.
    Ambarus CA, Noordenbos T, de Hair MJ, Tak PP, Baeten DL (2012) Intimal lining layer macrophages but not synovial sublining macrophages display an IL-10 polarized-like phenotype in chronic synovitis. Arthritis Res Ther 14:R74CrossRefGoogle Scholar
  19. 19.
    Myles A, Tuteja A, Aggarwal A (2012) Synovial fluid mononuclear cell gene expression profiling suggests dysregulation of innate immune genes in enthesitis-related arthritis patients. Rheumatology 51:1785–1789CrossRefGoogle Scholar
  20. 20.
    Kruithof E, Van den Bossche V, De Rycke L, Vandooren B, Joos R, Cañete JD, Tak PP, Boots AM, Veys EM, Baeten D (2006) Distinct synovial immunopathologic characteristics of juvenile-onset spondylarthritis and other forms of juvenile idiopathic arthritis. Arthritis Rheum 54:2594–2604CrossRefGoogle Scholar
  21. 21.
    Frings W, Dreier J, Sorg C (2002) Only the soluble form of the scavenger receptor CD163 acts inhibitory on phorbol ester-activated T-lymphocytes, whereas membrane-bound protein has no effect. FEBS Lett 526:93–96CrossRefGoogle Scholar
  22. 22.
    Moestrup SK, Moller HJ (2004) CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann Med 36:347–354CrossRefGoogle Scholar
  23. 23.
    Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK (2001) Identification of the haemoglobin scavenger receptor. Nature 409:198–201CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2019

Authors and Affiliations

  1. 1.Department of Clinical Immunology and RheumatologySanjay Gandhi Postgraduate Institute of Medical SciencesLucknowIndia

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