Dysregulated heme oxygenase-1 low M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons

Daiga Kishimoto, Yohei Kirino, Maasa Tamura, Mitsuhiro Takeno, Yosuke Kunishita, Kaoru Takase-Minegishi, Hiroto Nakano, Ikuma Kato, Kiyotaka Nagahama, Ryusuke Yoshimi, Kazuhiko Igarashi, Ichiro Aoki, Hideaki Nakajima

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34 Citations (Scopus)


Background: Innate immunity including macrophages (Mϕ) in lupus nephritis (LN) has been gaining attention, but roles of Mϕ in LN remain uncertain. Methods: Immunohistochemical 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. Results: The 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. Conclusions: Our 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.

Original languageEnglish
Article number64
JournalArthritis Research and Therapy
Issue number1
Publication statusPublished - 2018 Apr 10


  • Bach1
  • Heme oxygenase 1
  • Lupus nephritis
  • Macrophage polarization
  • Type I interferons


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