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NF‐E2–Related Factor 2 Regulates Interferon Receptor Expression and Alters Macrophage Polarization in Lupus
Author(s) -
Han Shuhong,
Zhuang Haoyang,
Lee Pui Y.,
Li Mingjia,
Yang Lijun,
Nigrovic Peter A.,
Reeves Westley H.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41383
Subject(s) - systemic lupus erythematosus , proinflammatory cytokine , inflammation , tumor necrosis factor alpha , gene expression , chemistry , activator (genetics) , interferon , receptor , immunology , endocrinology , medicine , biology , gene , biochemistry , disease
Objective Pristane‐induced lupus is associated with nonresolving inflammation and deficiency of proresolving macrophages. Proresolving nonclassic macrophages ( NCM s) are less responsive to type I interferon ( IFN ) than classic macrophages ( CM s; which are proinflammatory), reflecting their relative expression levels of the type I IFN receptor ( IFNAR ). This study was undertaken to investigate the regulation of IFNAR expression in macrophages. Methods We carried out gene expression profiling of purified CM s and NCM s from mice treated with pristane (which develop lupus) or mineral oil (non‐lupus controls). Macrophage differentiation and IFNAR expression were examined in mice treated with NF ‐E2–related factor 2 (Nrf2) activators and inhibitors and in Nrf2‐deficient mice. Nrf2 activity was also assessed in blood cells from patients with systemic lupus erythematosus ( SLE ). Significant differences were determined by Student's t ‐test. Results RNA sequencing revealed increased expression of genes regulated by the transcription factor Nrf2 in NCM s from mineral oil–treated versus pristane‐treated mice and in NCM s versus CM s. The Nrf2 activator CDDO ‐imidazole ( CDDO ‐Im) decreased CM s ( P < 0.0001) and promoted the development of proresolving NCM s ( P = 0.06), whereas the Nrf2 inhibitor brusatol increased CM s ( P < 0.05) and decreased NCM s ( P < 0.001). CDDO ‐Im decreased Ifnar1 ( P < 0.001) and IFN ‐stimulated gene ( ISG ) expression in macrophages and alleviated oxidative stress ( P < 0.05), whereas brusatol had the opposite effect ( P < 0.01). Moreover, Ifnar1 and ISG expression levels were higher in Nrf2‐knockout mice than controls ( P < 0.05). As seen in mice with lupus, SLE patients showed evidence of low Nrf2 activity. Conclusion Our findings indicate that Nrf2 activation favors the resolution of chronic inflammation in lupus. Since autoantibody production and lupus nephritis depend on IFNAR signaling, the ability of Nrf2 activators to repolarize macrophages and reduce the INF signature suggests that these agents may warrant consideration for treating lupus.