Amelioration of nephritis in receptor for advanced glycation end-products (RAGE)-deficient lupus-prone mice through neutrophil extracellular traps

Haruki Watanabe; Masataka Kubo; Akihiko Taniguchi; Yosuke Asano; Sumie Hiramatsu-Asano; Keiji Ohashi; Sonia Zeggar; Eri Katsuyama; Takayuki Katsuyama; Katsue Sunahori-Watanabe; Ken-Ei Sada; Yoshinori Matsumoto; Yasuhiko Yamamoto; Hiroshi Yamamoto; Myoungsun Son; Jun Wada

doi:10.1016/j.clim.2023.109317

Amelioration of nephritis in receptor for advanced glycation end-products (RAGE)-deficient lupus-prone mice through neutrophil extracellular traps

Clin Immunol. 2023 May:250:109317. doi: 10.1016/j.clim.2023.109317. Epub 2023 Apr 2.

Authors

Haruki Watanabe¹, Masataka Kubo², Akihiko Taniguchi³, Yosuke Asano², Sumie Hiramatsu-Asano², Keiji Ohashi², Sonia Zeggar², Eri Katsuyama², Takayuki Katsuyama², Katsue Sunahori-Watanabe², Ken-Ei Sada², Yoshinori Matsumoto², Yasuhiko Yamamoto⁴, Hiroshi Yamamoto⁵, Myoungsun Son⁶, Jun Wada²

Affiliations

¹ Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA. Electronic address: harukiw@okayama-u.ac.jp.
² Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
³ Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
⁴ Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
⁵ Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan; Komatsu University, Komatsu, Japan.
⁶ Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA.

Abstract

The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor that regulates inflammation, cell migration, and cell fate. Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease. To understand the function of RAGE in SLE, we generated RAGE-deficient (Ager^-/-) lupus-prone mice by backcrossing MRL/MpJ-Fas^lpr/J (MRL-lpr) mice with Ager^-/- C57BL/6 mice. In 18-week-old Ager^-/- MRL-lpr, the weights of the spleen and lymph nodes, as well as the frequency of CD3⁺CD4^-CD8^- cells, were significantly decreased. Ager^-/- MRL-lpr mice had significantly reduced urine albumin/creatinine ratios and markedly improved renal pathological scores. Moreover, neutrophil infiltration and neutrophil extracellular trap formation in the glomerulus were significantly reduced in Ager^-/- MRL-lpr. Our study is the first to reveal that RAGE can have a pathologic role in immune cells, particularly neutrophils and T cells, in inflammatory tissues and suggests that the inhibition of RAGE may be a potential therapeutic strategy for SLE.

Keywords: Lupus nephritis; Neutrophil extracellular traps; RAGE; Systemic lupus erythematosus.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Extracellular Traps*
Lupus Erythematosus, Systemic*
Lupus Nephritis*
Maillard Reaction
Mice
Mice, Inbred C57BL
Mice, Inbred MRL lpr
Receptor for Advanced Glycation End Products / genetics

Substances

Receptor for Advanced Glycation End Products

Grants and funding

R01 AI135063/AI/NIAID NIH HHS/United States