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조회849

연세대학교 의과대학, 세브란스병원

Kidney Int., 2023 Jul;104(1):163-180 | https://doi.org/10.1016/j.kint.2023.03.030 Macrophage transcription factor TonEBP promotes systemic lupus erythematosus and kidney injury via damage-induced signaling pathways

Eun Jin Yoo ^1,9, Kook-Hwan Oh ^2,9, Honglin Piao ^3,4, Hyun Je Kang ¹, Gyu Won Jeong ¹, Hyun Park ¹,Chang Jun Lee ¹, Hyunjin Ryu ², Seung Hee Yang ⁵, Myung-Gyu Kim ⁶, Dong Ki Kim ², Sung Ho Park ¹, Beom Jin Lim ⁷, Sang Min Lee ¹, Chan Young Park ¹, Soo Youn Choi ^1,8, Whaseon Lee-Kwon ¹, Jaeseok Yang ^3,10,* and Hyug Moo Kwon ^1,10,*

¹Department of Biological Sciences, UNIST, Ulsan, Republic of Korea
²Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
³Department of Internal Medicine, Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea
⁴Department of Medicine, Graduate School, Seoul National University College of Medicine, Seoul, Republic of Korea
⁵Kidney Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
⁶Department of Internal Medicine, Korea University Anam Hospital, Seoul, Republic of Korea
⁷Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
⁸Department of Biology, Jeju National University, Jeju, Republic of Korea
⁹EJY and K-HO are co–first authors.
¹⁰JY and HMK are co–senior authors.

*Corresponding author: correspondence to Jaeseok Yang or Hyug Moo Kwon

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by autoreactive B cells and dysregulation of many other types of immune cells including myeloid cells. Lupus nephritis (LN) is a common target organ manifestations of SLE. Tonicity-responsive enhancer-binding protein (TonEBP, also known as nuclear factor of activated T-cells 5 (NFAT5)), was initially identified as a central regulator of cellular responses to hypertonic stress and is a pleiotropic stress protein involved in a variety of immunometabolic diseases. To explore the role of TonEBP, we examined kidney biopsy samples from patients with LN. Kidney TonEBP expression was found to be elevated in these patients compared to control patients – in both kidney cells and infiltrating immune cells. Kidney TonEBP mRNA was elevated in LN and correlated with mRNAs encoding inflammatory cytokines and the degree of proteinuria. In a pristane-induced SLE model in mice, myeloid TonEBP deficiency blocked the development of SLE and LN. In macrophages, engagement of various toll-like receptors (TLRs) that respond to damage-associated molecular patterns induced TonEBP expression via stimulation of its promoter. Intracellular signaling downstream of the TLRs was dependent on TonEBP. Therefore, TonEBP can act as a transcriptional cofactor for NF-κB, and activated mTOR-IRF3/7 via protein-protein interactions. Additionally, TonEBP-deficient macrophages displayed elevated efferocytosis and animals with myeloid deficiency of TonEBP showed reduced Th1 and Th17 differentiation, consistent with macrophages defective in TLR signaling. Thus, our data show that myeloid TonEBP may be an attractive therapeutic target for SLE and LN.

논문정보

형식Research article
게재일2023년 07월 (BRIC 등록일 2023-07-11)
연구진국내 연구진
분야 생명과학 > 생리학

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