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

Olmes G, Büttner-Herold M, Ferrazzi F, Distel L, Amann K, Daniel C - Arthritis Res. Ther. (2016)

Bottom Line: 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.Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstr. 8-10, 91054, Erlangen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus

Tubular injury score (TSI) and glomerulosclerosis score (GSI) correlation with macrophage subtypes. TSI and GSI analyzed in renal biopsies from patients with lupus nephritis correlated with renal total, M2a-like and M2c-like macrophage invasion when analyzed by the Spearman test independently of the International Society of Nephrology/Renal Pathology Society class (a, c, e, g) and restricted to lupus nephritis (LN) class V (b, d, f, h). a Correlation between TSI in all patients with LN and total CD68-positive macrophages. b Correlation between TSI in patients with LN class V and total CD68-positive macrophages. c Correlation between TSI in all patients with LN and M2a-like macrophages. d Correlation between TSI in patients with LN class V and M2a-like macrophages. e Correlation between TSI in all patients with LN and M2c-like macrophages. f Correlation between TSI in patients withg LN class V and M2c-like macrophages. g Correlation between GSI in all patients with LN and total CD68-positive macrophages. h Correlation between GSI and patients with LN class V and total CD68-positive macrophages. Significant correlation is marked by asterisks (*p < 0.05; **p < 0.01)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4835936&req=5

Fig5: Tubular injury score (TSI) and glomerulosclerosis score (GSI) correlation with macrophage subtypes. TSI and GSI analyzed in renal biopsies from patients with lupus nephritis correlated with renal total, M2a-like and M2c-like macrophage invasion when analyzed by the Spearman test independently of the International Society of Nephrology/Renal Pathology Society class (a, c, e, g) and restricted to lupus nephritis (LN) class V (b, d, f, h). a Correlation between TSI in all patients with LN and total CD68-positive macrophages. b Correlation between TSI in patients with LN class V and total CD68-positive macrophages. c Correlation between TSI in all patients with LN and M2a-like macrophages. d Correlation between TSI in patients with LN class V and M2a-like macrophages. e Correlation between TSI in all patients with LN and M2c-like macrophages. f Correlation between TSI in patients withg LN class V and M2c-like macrophages. g Correlation between GSI in all patients with LN and total CD68-positive macrophages. h Correlation between GSI and patients with LN class V and total CD68-positive macrophages. Significant correlation is marked by asterisks (*p < 0.05; **p < 0.01)

Mentions: In our cohort of patients with SLE we found that renal injury is associated with most of the investigated macrophage subtypes. In the tubulointerstitium there was positive correlation between a higher TSI and the number of total CD68+ macrophages (r = 0.328; Fig. 5a) but also with the number of M2a-like (r = 0.446; Fig. 5c) and M2c-like macrophages (r = 0.420; Fig. 5e) when correlation with the TSI was tested independently of ISN/RPS lupus class. In contrast, there was no correlation between the TSI and the number of M1-like macrophages. Interestingly, there was stronger correlation with TSI when the analysis was restricted to class V patients (Fig. 5b, d, f). Sub-analysis of other lupus nephritis (LN) classes revealed only significant correlation) between TSI and M2c-like macrophages in ISN/RPS class IV patients (r = 0.550, p = 0.015). Furthermore, a higher GSI correlated with the number of most of the investigated macrophage subtypes within the glomeruli, including total CD68+ macrophages (r = 0.369; Fig. 5g), CD206+ M2a-like macrophages (r = 0.280; p < 0.05), CD163+ M2c-macrophages (r = 0,333; p < 0.01) and only weakly with iNOS+ M1-like macrophages (r = 0.263; p = 0.03). Again, on sub-analysis of LN class V patients, there was stronger correlation between total CD68+ macrophages and GSI (Fig. 5h). There was weak correlation between crescent formation (a sign of active glomerular damage) and the number of glomerular total CD68+ macrophages (r = 0.302; p = 0.012) and between crescent formation and glomerular CD163+ M2c-like macrophages (r = 0.318, p = 0.008). Interestingly, there was strong positive correlation between the Austin activity score (Table 1) and glomerular (r = 0.549; p < 0.001) and tubulointerstitial (r = 0.550; p < 0.001) CD68+ macrophages and M2c-like glomerular (r = 0.382; p = 0.005) and tubulointerstitial macrophages (r = 0.525; p < 0.001) but no correlation between Austin score and M1-like and M2a-like macrophages in either compartment. Macrophages are also known to exert pro-fibrotic properties; therefore, we investigated interstitial fibrosis and tubular atrophy (IFTA) in renal biopsies. The number of tubulointerstitial M2a-like and M2c-like macrophages were similarly correlated (r = 0,360 and 0,355, p < 0,005) with IFTA.Fig. 5


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

Olmes G, Büttner-Herold M, Ferrazzi F, Distel L, Amann K, Daniel C - Arthritis Res. Ther. (2016)

Tubular injury score (TSI) and glomerulosclerosis score (GSI) correlation with macrophage subtypes. TSI and GSI analyzed in renal biopsies from patients with lupus nephritis correlated with renal total, M2a-like and M2c-like macrophage invasion when analyzed by the Spearman test independently of the International Society of Nephrology/Renal Pathology Society class (a, c, e, g) and restricted to lupus nephritis (LN) class V (b, d, f, h). a Correlation between TSI in all patients with LN and total CD68-positive macrophages. b Correlation between TSI in patients with LN class V and total CD68-positive macrophages. c Correlation between TSI in all patients with LN and M2a-like macrophages. d Correlation between TSI in patients with LN class V and M2a-like macrophages. e Correlation between TSI in all patients with LN and M2c-like macrophages. f Correlation between TSI in patients withg LN class V and M2c-like macrophages. g Correlation between GSI in all patients with LN and total CD68-positive macrophages. h Correlation between GSI and patients with LN class V and total CD68-positive macrophages. Significant correlation is marked by asterisks (*p < 0.05; **p < 0.01)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835936&req=5

Fig5: Tubular injury score (TSI) and glomerulosclerosis score (GSI) correlation with macrophage subtypes. TSI and GSI analyzed in renal biopsies from patients with lupus nephritis correlated with renal total, M2a-like and M2c-like macrophage invasion when analyzed by the Spearman test independently of the International Society of Nephrology/Renal Pathology Society class (a, c, e, g) and restricted to lupus nephritis (LN) class V (b, d, f, h). a Correlation between TSI in all patients with LN and total CD68-positive macrophages. b Correlation between TSI in patients with LN class V and total CD68-positive macrophages. c Correlation between TSI in all patients with LN and M2a-like macrophages. d Correlation between TSI in patients with LN class V and M2a-like macrophages. e Correlation between TSI in all patients with LN and M2c-like macrophages. f Correlation between TSI in patients withg LN class V and M2c-like macrophages. g Correlation between GSI in all patients with LN and total CD68-positive macrophages. h Correlation between GSI and patients with LN class V and total CD68-positive macrophages. Significant correlation is marked by asterisks (*p < 0.05; **p < 0.01)
Mentions: In our cohort of patients with SLE we found that renal injury is associated with most of the investigated macrophage subtypes. In the tubulointerstitium there was positive correlation between a higher TSI and the number of total CD68+ macrophages (r = 0.328; Fig. 5a) but also with the number of M2a-like (r = 0.446; Fig. 5c) and M2c-like macrophages (r = 0.420; Fig. 5e) when correlation with the TSI was tested independently of ISN/RPS lupus class. In contrast, there was no correlation between the TSI and the number of M1-like macrophages. Interestingly, there was stronger correlation with TSI when the analysis was restricted to class V patients (Fig. 5b, d, f). Sub-analysis of other lupus nephritis (LN) classes revealed only significant correlation) between TSI and M2c-like macrophages in ISN/RPS class IV patients (r = 0.550, p = 0.015). Furthermore, a higher GSI correlated with the number of most of the investigated macrophage subtypes within the glomeruli, including total CD68+ macrophages (r = 0.369; Fig. 5g), CD206+ M2a-like macrophages (r = 0.280; p < 0.05), CD163+ M2c-macrophages (r = 0,333; p < 0.01) and only weakly with iNOS+ M1-like macrophages (r = 0.263; p = 0.03). Again, on sub-analysis of LN class V patients, there was stronger correlation between total CD68+ macrophages and GSI (Fig. 5h). There was weak correlation between crescent formation (a sign of active glomerular damage) and the number of glomerular total CD68+ macrophages (r = 0.302; p = 0.012) and between crescent formation and glomerular CD163+ M2c-like macrophages (r = 0.318, p = 0.008). Interestingly, there was strong positive correlation between the Austin activity score (Table 1) and glomerular (r = 0.549; p < 0.001) and tubulointerstitial (r = 0.550; p < 0.001) CD68+ macrophages and M2c-like glomerular (r = 0.382; p = 0.005) and tubulointerstitial macrophages (r = 0.525; p < 0.001) but no correlation between Austin score and M1-like and M2a-like macrophages in either compartment. Macrophages are also known to exert pro-fibrotic properties; therefore, we investigated interstitial fibrosis and tubular atrophy (IFTA) in renal biopsies. The number of tubulointerstitial M2a-like and M2c-like macrophages were similarly correlated (r = 0,360 and 0,355, p < 0,005) with IFTA.Fig. 5

Bottom Line: 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.Interestingly, in hypertensive lupus patients only the number of M2a-like macrophages was significantly increased compared to biopsies from normotensive lupus patients.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Krankenhausstr. 8-10, 91054, Erlangen, Germany.

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.

No MeSH data available.


Related in: MedlinePlus