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Open Access 01-12-2018 | Research article

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

Authors: 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

Published in: Arthritis Research & Therapy | Issue 1/2018

Abstract

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.

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Title: Dysregulated heme oxygenase-1low M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons
Authors: 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
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2018
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-018-1568-1

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

Abstract

Background

Methods

Results

Conclusions

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