Abstract
BackgroundThe 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.MethodUsing 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.ResultsThe 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.ConclusionM2-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.
Highlights
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
Macrophages can be divided into two major classes: the classical activated M1-like macrophages, representing a proinflammatory type expressing the marker inducible nitric oxide synthase [18] and the alternatively activated M2-like-macrophages, which can be subdivided into M2a-like macrophages that are involved in repair and progression of fibrosis [19], M2b-like macrophages that are inducible by immune complexes and lipopolysaccharide (LPS) regulating immune response [20], and M2c-like macrophages exerting antiinflammatory and pro-fibrotic actions [21]
Crescent formation was absent in International Society of Nephrology/Renal Pathology Society (ISN/RPS) classes II and V and class IV biopsies had the highest prevalence of crescent formation (Table 1)
Summary
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. Major mechanisms initiating the inflammatory response in lupus nephritis are the production of autoantibodies and complement activation, but cellular immune mechanisms mediated through infiltrating mononuclear cells including macrophages have an important role in amplification and progression of renal injury in SLE [3]. Much work has been done to elucidate the pathophysiology of and optimal therapy for SLE, focused on the role of autoimmune B cells, T cells, and plasma cells It has become evident, that macrophages are important players in the pathogenesis of lupus nephritis. Macrophages can be divided into two major classes: the classical activated M1-like macrophages, representing a proinflammatory type expressing the marker inducible nitric oxide synthase (iNOS) [18] and the alternatively activated M2-like-macrophages, which can be subdivided into M2a-like macrophages that are involved in repair and progression of fibrosis [19], M2b-like macrophages that are inducible by immune complexes and lipopolysaccharide (LPS) regulating immune response [20], and M2c-like macrophages exerting antiinflammatory and pro-fibrotic actions [21]
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