CD163+ M2c-like Macrophages Predominate in Renal Biopsies from Patients with Lupus Nephritis

Overview

Journal Arthritis Res Ther

Publisher Biomed Central

Specialty Rheumatology

Date 2016 Apr 20

PMID 27091114

Citations 59

Authors

Gregor Olmes

Maike Buttner-Herold

Fulvia Ferrazzi

Luitpold Distel

Kerstin Amann

Christoph Daniel

Affiliations

Soon will be listed here.

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.

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References

Hagiwara E, Gourley M, Lee S, Klinman D . 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. DOI: 10.1002/art.1780390305. View

Hashimoto-Kataoka T, Hosen N, Sonobe T, Arita Y, Yasui T, Masaki T . 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. PMC: 4443312. DOI: 10.1073/pnas.1424774112. View

Bignon A, Gaudin F, Hemon P, Tharinger H, Mayol K, Walzer T . CCR1 inhibition ameliorates the progression of lupus nephritis in NZB/W mice. J Immunol. 2013; 192(3):886-96. DOI: 10.4049/jimmunol.1300123. View

Zizzo G, Hilliard B, Monestier M, Cohen P . Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol. 2012; 189(7):3508-20. PMC: 3465703. DOI: 10.4049/jimmunol.1200662. View

You H, Gao T, Cooper T, Reeves W, Awad A . Macrophages directly mediate diabetic renal injury. Am J Physiol Renal Physiol. 2013; 305(12):F1719-27. PMC: 3882451. DOI: 10.1152/ajprenal.00141.2013. View

Ko G, Boo C, Jo S, Cho W, Kim H . Macrophages contribute to the development of renal fibrosis following ischaemia/reperfusion-induced acute kidney injury. Nephrol Dial Transplant. 2007; 23(3):842-52. DOI: 10.1093/ndt/gfm694. View

Hainz N, Thomas S, Neubert K, Meister S, Benz K, Rauh M . 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. DOI: 10.1159/000334955. View

Ohlsson S, Linge C, Gullstrand B, Lood C, Johansson A, Ohlsson S . Serum from patients with systemic vasculitis induces alternatively activated macrophage M2c polarization. Clin Immunol. 2014; 152(1-2):10-9. DOI: 10.1016/j.clim.2014.02.016. View

Paulus P, Holfeld J, Urbschat A, Mutlak H, Ockelmann P, Tacke S . Prednisolone as preservation additive prevents from ischemia reperfusion injury in a rat model of orthotopic lung transplantation. PLoS One. 2013; 8(8):e73298. PMC: 3756949. DOI: 10.1371/journal.pone.0073298. View

10.

Li J, Liu C, Xu D, Gao B . Significance of CD163-Positive Macrophages in Proliferative Glomerulonephritis. Am J Med Sci. 2015; 350(5):387-92. DOI: 10.1097/MAJ.0000000000000569. View

11.

Chan C, Moore J, Budzyn K, Guida E, Diep H, Vinh A . Reversal of vascular macrophage accumulation and hypertension by a CCR2 antagonist in deoxycorticosterone/salt-treated mice. Hypertension. 2012; 60(5):1207-12. DOI: 10.1161/HYPERTENSIONAHA.112.201251. View

12.

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. DOI: 10.3109/08820139.2014.909458. View

13.

Lapuc I, Bolkun L, Eljaszewicz A, Rusak M, Luksza E, Singh P . 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. DOI: 10.3892/or.2015.4088. View

14.

Ryan M . The pathophysiology of hypertension in systemic lupus erythematosus. Am J Physiol Regul Integr Comp Physiol. 2009; 296(4):R1258-67. PMC: 2698608. DOI: 10.1152/ajpregu.90864.2008. View

15.

Kriska T, Cepura C, Magier D, Siangjong L, Gauthier K, Campbell W . Mice lacking macrophage 12/15-lipoxygenase are resistant to experimental hypertension. Am J Physiol Heart Circ Physiol. 2012; 302(11):H2428-38. PMC: 3378305. DOI: 10.1152/ajpheart.01120.2011. View

16.

Brugos B, Vincze Z, Sipka S, Szegedi G, Zeher M . Serum and urinary cytokine levels of SLE patients. Pharmazie. 2012; 67(5):411-3. View

17.

Guillen-Gomez E, Guirado L, Belmonte X, Maderuelo A, Santin S, Juarez C . Monocyte implication in renal allograft dysfunction. Clin Exp Immunol. 2013; 175(2):323-31. PMC: 3892423. DOI: 10.1111/cei.12228. View

18.

Hasegawa H, Kohno M, Sasaki M, Inoue A, Ito M, Terada M . 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. DOI: 10.1002/art.11231. View

19.

Guo Z, Parimi V, OMalley M, Thirunavukarasu P, Sathaiah M, Austin F . 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. PMC: 2982886. DOI: 10.1038/gt.2010.104. View

20.

Perez De Lema G, Maier H, Franz T, Escribese M, Chilla S, Segerer S . 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. DOI: 10.1681/ASN.2005040426. View