Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

CD163+ M2c-like macrophages predominate in renal biopsies from patients with lupus nephritis

Authors: Gregor Olmes, Maike Büttner-Herold, Fulvia Ferrazzi, Luitpold Distel, Kerstin Amann, Christoph Daniel

Published in: Arthritis Research & Therapy | Issue 1/2016

Login to get access

Abstract

Background

The role of macrophages in the pathogenesis of lupus nephritis, in particular their differentiation to a certain subtype (e.g., M1- or M2-like) modulating the inflammatory reaction, is unknown. Here we investigated whether the differentiation in M1- or M2-like macrophages depends on the stage of lupus nephritis and whether this correlates with clinical parameters.

Method

Using immunohistochemical analysis we analyzed renal biopsies from 68 patients with lupus nephritis (ISN/RPS classes II–V) for infiltration with M1-like (iNOS+/CD68+), M2a-like (CD206+/CD68+), M2c-like macrophages (CD163+/CD68+), and FoxP3+ regulatory T-cells. In addition, clinical parameters at the time of renal biopsy, i.e., blood pressure, proteinuria and serum urea were correlated with the macrophage infiltration using the Spearman test.

Results

The mean number of CD68+ macrophages was related to the diagnosed ISN/RPS class, showing the highest macrophage infiltration in biopsies with diffuse class IV and the lowest number in ISN/RPS class V. In all ISN/RPS classes we detected more M2c-like CD163+/CD68+ than M2a-like CD206+/CD68+ cells, while M1-macrophages played only a minor role. Cluster analysis using macrophage subtype numbers in different renal compartments revealed three main clusters showing cluster 1 dominated by class V. Clusters 2 and 3 were dominated by lupus class IV indicating that this class can be further differentiated by its macrophage population. The number of tubulointerstitial FoxP3+ cells correlated with all investigated macrophage subtypes showing the strongest association to numbers of M2a-like macrophages. Kidney function, as assessed by serum creatinine and serum urea, correlated positively with the number of total CD68+, M2a-like and M2c-like macrophages in the tubulointerstitium. In addition, total CD68+ and M2c-like macrophage numbers highly correlated with Austin activity score. Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients.

Conclusion

M2-like macrophages are the dominant subpopulation in human lupus nephritis and particularly, M2a subpopulations were associated with disease progression, but their role in disease progression remains unclear.
Literature
1.
Maroz N, Segal MS. Lupus nephritis and end-stage kidney disease. Am J Med Sci. 2013;346(4):319–23.CrossRefPubMed
2.
Weening JJ, D’Agati VD, Schwartz MM, Seshan SV, Alpers CE, Appel GB, Balow JE, Bruijn JA, Cook T, Ferrario F et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. 2004;15(2):241–50.
3.
Kuroiwa T, Lee EG. Cellular interactions in the pathogenesis of lupus nephritis: the role of T cells and macrophages in the amplification of the inflammatory process in the kidney. Lupus. 1998;7(9):597–603.CrossRefPubMed
4.
Bergtold A, Gavhane A, D’Agati V, Madaio M, Clynes R. FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis. J Immunol. 2006;177(10):7287–95.CrossRefPubMed
5.
Biermann MH, Veissi S, Maueroder C, Chaurio R, Berens C, Herrmann M, Munoz LE. The role of dead cell clearance in the etiology and pathogenesis of systemic lupus erythematosus: dendritic cells as potential targets. Expert Rev Clin Immunol. 2014;10(9):1151–64.
6.
Tucci M, Stucci S, Strippoli S, Silvestris F. Cytokine overproduction, T-cell activation, and defective T-regulatory functions promote nephritis in systemic lupus erythematosus. J Biomed Biotechnol. 2010;2010:457146.CrossRefPubMedPubMedCentral
7.
Williams TM, Little MH, Ricardo SD. Macrophages in renal development, injury, and repair. Semin Nephrol. 2010;30(3):255–67.CrossRefPubMed
8.
Chalmers SA, Chitu V, Herlitz LC, Sahu R, Stanley ER, Putterman C. Macrophage depletion ameliorates nephritis induced by pathogenic antibodies. J Autoimmun. 2015;57:42–52.CrossRefPubMedPubMedCentral
9.
Ferenbach DA, Sheldrake TA, Dhaliwal K, Kipari TM, Marson LP, Kluth DC, Hughes J. Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice. Kidney Int. 2012;82(8):928–33.
10.
Ko GJ, Boo CS, Jo SK, Cho WY, Kim HK. Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury. Nephrol Dial Transplant. 2008;23(3):842–52.CrossRefPubMed
11.
Vielhauer V, Kulkarni O, Reichel CA, Anders HJ. Targeting the recruitment of monocytes and macrophages in renal disease. Semin Nephrol. 2010;30(3):318–33.CrossRefPubMed
12.
Hasegawa H, Kohno M, Sasaki M, Inoue A, Ito MR, Terada M, Hieshima K, Maruyama H, Miyazaki J, Yoshie O et al. Antagonist of monocyte chemoattractant protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice. Arthritis Rheum. 2003;48(9):2555–66.
13.
Bignon A, Gaudin F, Hemon P, Tharinger H, Mayol K, Walzer T, Loetscher P, Peuchmaur M, Berrebi D, Balabanian K. CCR1 inhibition ameliorates the progression of lupus nephritis in NZB/W mice. J Immunol. 2014;192(3):886–96.
14.
Liu H, Diao C, Wu C, Xia L, Duan H, Fang F, Ding S, Xiao W. Anti-macrophage-derived chemokine antibody relieves murine lupus nephritis. Rheumatol Int. 2011;31(11):1459–64.
15.
Perez de Lema G, Maier H, Franz TJ, Escribese M, Chilla S, Segerer S, Camarasa N, Schmid H, Banas B, Kalaydjiev S et al. Chemokine receptor Ccr2 deficiency reduces renal disease and prolongs survival in MRL/lpr lupus-prone mice. J Am Soc Nephrol. 2005;16(12):3592–601.
16.
Tanaka H, Oki E, Tsuruga K, Aizawa-Yashiro T, Ito Y, Sato N, Kawasaki Y, Suzuki J. Mizoribine attenuates renal injury and macrophage infiltration in patients with severe lupus nephritis. Clin Rheumatol. 2010;29(9):1049–54.
17.
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.CrossRefPubMed
18.
Ndisang JF, Mishra M. The heme oxygenase system selectively suppresses the proinflammatory macrophage m1 phenotype and potentiates insulin signaling in spontaneously hypertensive rats. Am J Hypertens. 2013;26(9):1123–31.CrossRefPubMed
19.
Anders HJ, Ryu M. Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. Kidney Int. 2011;80(9):915–25.CrossRefPubMed
20.
Sironi M, Martinez FO, D’Ambrosio D, Gattorno M, Polentarutti N, Locati M, Gregorio A, Iellem A, Cassatella MA, Van Damme J et al. Differential regulation of chemokine production by Fcgamma receptor engagement in human monocytes: association of CCL1 with a distinct form of M2 monocyte activation (M2b, Type 2). J Leukoc Biol. 2006;80(2):342–9.
21.
Lu J, Cao Q, Zheng D, Sun Y, Wang C, Yu X, Wang Y, Lee VW, Zheng G, Tan TK et al. Discrete functions of M2a and M2c macrophage subsets determine their relative efficacy in treating chronic kidney disease. Kidney Int. 2013;84(4):745–55.
22.
Zizzo G, Guerrieri J, Dittman LM, Merrill JT, Cohen PL. Circulating levels of soluble MER in lupus reflect M2c activation of monocytes/macrophages, autoantibody specificities and disease activity. Arthritis Res Ther. 2013;15(6):R212.CrossRefPubMedPubMedCentral
23.
Iwata Y, Bostrom EA, Menke J, Rabacal WA, Morel L, Wada T, Kelley VR. Aberrant macrophages mediate defective kidney repair that triggers nephritis in lupus-susceptible mice. J Immunol. 2012;188(9):4568–80.
24.
Sahu R, Bethunaickan R, Singh S, Davidson A. Structure and function of renal macrophages and dendritic cells from lupus-prone mice. Arthritis Rheumatol. 2014;66(6):1596–607.CrossRefPubMedPubMedCentral
25.
Orme J, Mohan C. Macrophage subpopulations in systemic lupus erythematosus. Discov Med. 2012;13(69):151–8.PubMed
26.
Ciccia F, Alessandro R, Rizzo A, Accardo-Palumbo A, Raimondo S, Raiata F, Guggino G, Giardina A, De Leo G, Sireci G et al. Macrophage phenotype in the subclinical gut inflammation of patients with ankylosing spondylitis. Rheumatology (Oxford). 2014;53(1):104–13.
27.
Edin S, Wikberg ML, Dahlin AM, Rutegard J, Oberg A, Oldenborg PA, Palmqvist R. The distribution of macrophages with a M1 or M2 phenotype in relation to prognosis and the molecular characteristics of colorectal cancer. PLoS One. 2012;7(10):e47045.
28.
Gensel JC, Zhang B. Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res. 2015;1619:1–11.CrossRefPubMed
29.
You H, Gao T, Cooper TK, Brian Reeves W, Awad AS. Macrophages directly mediate diabetic renal injury. Am J Physiol Renal Physiol. 2013;305(12):F1719–27.CrossRefPubMedPubMedCentral
30.
Ohlsson SM, Linge CP, Gullstrand B, Lood C, Johansson A, Ohlsson S, Lundqvist A, Bengtsson AA, Carlsson F, Hellmark T. Serum from patients with systemic vasculitis induces alternatively activated macrophage M2c polarization. Clin Immunol. 2014;152(1-2):10–9.
31.
Hainz N, Thomas S, Neubert K, Meister S, Benz K, Rauh M, Daniel C, Wiesener M, Voll RE, Amann K. The proteasome inhibitor bortezomib prevents lupus nephritis in the NZB/W F1 mouse model by preservation of glomerular and tubulointerstitial architecture. Nephron Exp Nephrol. 2012;120(2):e47–58.
32.
Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008;8(4):753–60.
33.
Austin 3rd HA, Muenz LR, Joyce KM, Antonovych TT, Balow JE. Diffuse proliferative lupus nephritis: identification of specific pathologic features affecting renal outcome. Kidney Int. 1984;25(4):689–95.CrossRefPubMed
34.
Li J, Liu CH, Xu DL, Gao B. Significance of CD163-positive macrophages in proliferative glomerulonephritis. Am J Med Sci. 2015;350(5):387–92.CrossRefPubMed
35.
Brugos B, Vincze Z, Sipka S, Szegedi G, Zeher M. Serum and urinary cytokine levels of SLE patients. Pharmazie. 2012;67(5):411–3.PubMed
36.
Cigni A, Pileri PV, Faedda R, Gallo P, Sini A, Satta AE, Marras R, Carta E, Argiolas D, Rum I et al. Interleukin 1, interleukin 6, interleukin 10, and tumor necrosis factor alpha in active and quiescent systemic lupus erythematosus. J Investig Med. 2014;62(5):825–9.
37.
Tang Z, Niven-Fairchild T, Tadesse S, Norwitz ER, Buhimschi CS, Buhimschi IA, Guller S. Glucocorticoids enhance CD163 expression in placental Hofbauer cells. Endocrinology. 2013;154(1):471–82.
38.
Paulus P, Holfeld J, Urbschat A, Mutlak H, Ockelmann PA, Tacke S, Zacharowski K, Reissig C, Stay D, Scheller B. Prednisolone as preservation additive prevents from ischemia reperfusion injury in a rat model of orthotopic lung transplantation. PLoS One. 2013;8(8):e73298.
39.
Sekerkova A, Krepsova E, Brabcova E, Slatinska J, Viklicky O, Lanska V, Striz I. CD14 + CD16+ and CD14 + CD163+ monocyte subpopulations in kidney allograft transplantation. BMC Immunol. 2014;15:4.
40.
Guo ZS, Parimi V, O’Malley ME, Thirunavukarasu P, Sathaiah M, Austin F, Bartlett DL. The combination of immunosuppression and carrier cells significantly enhances the efficacy of oncolytic poxvirus in the pre-immunized host. Gene Ther. 2010;17(12):1465–75.
41.
Lapuc I, Bolkun L, Eljaszewicz A, Rusak M, Luksza E, Singh P, Miklasz P, Piszcz J, Ptaszynska-Kopczynska K, Jasiewicz M et al. Circulating classical CD14++CD16- monocytes predict shorter time to initial treatment in chronic lymphocytic leukemia patients: differential effects of immune chemotherapy on monocyte-related membrane and soluble forms of CD163. Oncol Rep. 2015;34(3):1269–78.
42.
Hagiwara E, Gourley MF, Lee S, Klinman DK. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10:interferon-gamma-secreting cells in the peripheral blood. Arthritis Rheum. 1996;39(3):379–85.CrossRefPubMed
43.
Zizzo G, Hilliard BA, Monestier M, Cohen PL. Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol. 2012;189(7):3508–20.CrossRefPubMedPubMedCentral
44.
Hill GS, Delahousse M, Nochy D, Remy P, Mignon F, Mery JP, Bariety J. Predictive power of the second renal biopsy in lupus nephritis: significance of macrophages. Kidney Int. 2001;59(1):304–16.
45.
Gutierrez E, Egido J, Rubio-Navarro A, Buendia I, Blanco Colio LM, Toldos O, Manzarbeitia F, de Lorenzo A, Sanchez R, Ortiz A et al. Oxidative stress, macrophage infiltration and CD163 expression are determinants of long-term renal outcome in macrohematuria-induced acute kidney injury of IgA nephropathy. Nephron Clin Pract. 2012;121(1-2):c42–53.
46.
Guillen-Gomez E, Guirado L, Belmonte X, Maderuelo A, Santin S, Juarez C, Ars E, Facundo C, Ballarin JA, Vidal S et al. Monocyte implication in renal allograft dysfunction. Clin Exp Immunol. 2014;175(2):323–31.
47.
Nakayama W, Jinnin M, Makino K, Kajihara I, Makino T, Fukushima S, Sakai K, Inoue Y, Ihn H. CD163 expression is increased in the involved skin and sera of patients with systemic lupus erythematosus. Eur J Dermatol. 2012;22(4):512–7.
48.
Wang J, Jiang ZP, Su N, Fan JJ, Ruan YP, Peng WX, Li YF, Yu XQ. The role of peritoneal alternatively activated macrophages in the process of peritoneal fibrosis related to peritoneal dialysis. Int J Mol Sci. 2013;14(5):10369–82.
49.
Evans BJ, Haskard DO, Sempowksi G, Landis RC. Evolution of the Macrophage CD163 Phenotype and Cytokine Profiles in a Human Model of Resolving Inflammation. Int J Inflamm. 2013;2013:780502.CrossRef
50.
Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger Jr TA, Jansen-McWilliams L, D'Agostino RB, Kuller LH. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol. 1997;145(5):408–15.
51.
52.
Chan CT, Moore JP, Budzyn K, Guida E, Diep H, Vinh A, Jones ES, Widdop RE, Armitage JA, Sakkal S et al. Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice. Hypertension. 2012;60(5):1207–12.
53.
Kriska T, Cepura C, Magier D, Siangjong L, Gauthier KM, Campbell WB. Mice lacking macrophage 12/15-lipoxygenase are resistant to experimental hypertension. Am J Physiol Heart Circ Physiol. 2012;302(11):H2428–38.CrossRefPubMedPubMedCentral
54.
Hashimoto-Kataoka T, Hosen N, Sonobe T, Arita Y, Yasui T, Masaki T, Minami M, Inagaki T, Miyagawa S, Sawa Y et al. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A. 2015;112(20):E2677–86.
55.
Qian L, Li X, Fang R, Wang Z, Xu Y, Zhang H, Bai H, Yang Q, Zhu X, Ben J et al. Class A scavenger receptor deficiency augments angiotensin II-induced vascular remodeling. Biochem Pharmacol. 2014;90(3):254–64.
56.
Kinsey GR, Sharma R, Huang L, Li L, Vergis AL, Ye H, Ju ST, Okusa MD. Regulatory T cells suppress innate immunity in kidney ischemia-reperfusion injury. J Am Soc Nephrol. 2009;20(8):1744–53.
57.
Hu K, Zhou H, Zheng G, Wang G, Fu Y, Jiang Y. Imbalance of different types of CD4(+)Foxp3(+) T cells in renal transplant recipients. Immunol Invest. 2014;43(8):838–50.CrossRefPubMed
Metadata
Title
CD163+ M2c-like macrophages predominate in renal biopsies from patients with lupus nephritis
Authors
Gregor Olmes
Maike Büttner-Herold
Fulvia Ferrazzi
Luitpold Distel
Kerstin Amann
Christoph Daniel
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-0989-y

Other articles of this Issue 1/2016

Arthritis Research & Therapy 1/2016 Go to the issue

Research article

Randomized controlled studies on the efficacy of antiarthritic agents in inhibiting cartilage degeneration and pain associated with progression of osteoarthritis in the rat

Research article

Anti-citrullinated protein antibodies and high levels of rheumatoid factor are associated with systemic bone loss in patients with early untreated rheumatoid arthritis

Research article

Power Doppler ultrasonographic assessment of the joint-draining lymph node complex in rheumatoid arthritis: a prospective, proof-of-concept study on treatment with tumor necrosis factor inhibitors

Research article

Circadian variations in clinical symptoms and concentrations of inflammatory cytokines, melatonin, and cortisol in polymyalgia rheumatica before and during prednisolone treatment: a controlled, observational, clinical experimental study

Research article

Urate crystal deposition and bone erosion in gout: ‘inside-out’ or ‘outside-in’? A dual-energy computed tomography study

Research article

Reduced induction of anti-PF4/heparin antibody in RA patients after total knee arthroplasty
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits