Abstract
BackgroundInnate immunity including macrophages (Mϕ) in lupus nephritis (LN) has been gaining attention, but roles of Mϕ in LN remain uncertain.MethodsImmunohistochemical staining was performed to determine CD68, CD163, heme oxygenase (HO)-1 (a stress-inducible heme-degrading enzyme with anti-inflammatory property), pSTAT1, and CMAF-expressing Mϕ in the glomeruli of patients with LN. Effects of type I interferons on the expression levels of CD163, HO-1, BTB and CNC homology 1 (Bach1; a transcriptional HO-1 repressor), interleukin (IL)-6, and IL-10 by human M2-like Mϕ, which were differentiated in vitro from peripheral monocytes with macrophage colony-stimulating factor, were assessed by RT-PCR and immunocytostaining. Clinical manifestations, anti-double-stranded DNA (anti-dsDNA), and local HO-1 expression were compared in Bach1-deficient and wild-type MRL/lpr mice.ResultsThe number of glomerular M2-like Mϕ correlated with the amounts of proteinuria in patients with LN. Unlike monocyte-derived M2-like Mϕ, HO-1 expression was defective in the majority of glomerular M2-like Mϕ of patients with LN. Stimulation of human M2-like Mϕ with type I interferons led to reduced HO-1 expression and increased Bach1 and IL-6 expression. Bach1-deficient MRL/lpr mice exhibited increased HO-1 expression in kidneys, prolonged survival, reduced urine proteins, and serum blood urea nitrogen levels, but serum anti-dsDNA antibody levels were comparable. Increased expression of CD163 and HO-1 was found in peritoneal Mϕ from Bach1-deficient MRL/lpr mice.ConclusionsOur data suggest that dysregulated M2-like Mϕ play a proinflammatory role in LN. Bach1 is a potential therapeutic target that could restore the anti-inflammatory property of M2 Mϕ.
Highlights
Innate immunity including macrophages (Mφ) in lupus nephritis (LN) has been gaining attention, but roles of Mφ in LN remain uncertain
We found that numbers of CD163+ cells were comparable to numbers of CD68+ cells in the glomerulus of LN
We focused on effects of IFN-α on messenger RNA (mRNA) expression of both molecules in human monocyte-derived M2-like Mφ generated in vitro, because type I IFN and the related genes are upregulated in patients with LN, including the renal tissues as a so-called IFN signature [1, 3, 30]
Summary
Innate immunity including macrophages (Mφ) in lupus nephritis (LN) has been gaining attention, but roles of Mφ in LN remain uncertain. Lupus nephritis (LN) occurs in approximately 25–50% of patients with SLE and remains one of the leading causes of morbidity [2]. New immunosuppressive therapies such as mycophenolate mofetil have been improving disease. In renal biopsy specimens from patients with LN, M2c Mφ (CD68+/CD163+) predominates over M1 Mφ (CD68+/inducible nitric oxide synthase-positive) [10]. These data suggest potential roles of M2 Mφ in LN
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