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Paeoniflorin ameliorates murine lupus nephritis by increasing CD4+Foxp3+ Treg cells via enhancing mTNFα-TNFR2 pathway.

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机构: [1]Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, and the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China [2]Department of Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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关键词: Lupus nephritis Paeoniflorin Macrophage TNF-α /TNFR2 Treg

摘要:
Treg cells are essential for re-establishing self-tolerance in lupus. However, given that direct Treg therapies may be inadequate to control autoimmunity and inflammation, a strategy of inducing or expanding endogenous Treg cells in vivo may be a good option. Macrophages are main tissue-infiltrating cells and play a role in promoting Treg differentiation while paeoniflorin (PF), a monoterpene glycoside, exhibits anti-inflammatory and immunoregulatory effects. Here, we studied the effects of PF on CD4+FoxP3+ Treg frequency and the potential mechanisms involving M2 macrophages. We demonstrated that PF ameliorated lupus nephritis in lupus-prone B6/gld mice by reducing urinary protein, serum creatinine and anti-dsDNA levels, diminishing renal cellular infiltration, improving renal immunopathology and downregulating renal gene and protein expressions of key cytokines, including IFN-γ, IL-6, IL-12 and IL-23. PF also lowered the percentage of CD44highCD62Llow effector T cells while augmenting CD4+FoxP3+ Treg frequency in B6/gld mice. Importantly, PF increased TNFR2 expression on CD4+FoxP3+ Tregs, but not CD4+FoxP3- T cells, in vivo and in vitro. Furthermore, we found that CD206+ subset of F4/80+CD11b+ macrophages expressed a higher level of mTNF-α than their CD206- counterparts while PF increased mTNF-α expression on CD206+ macrophages in vitro and in vivo. In vitro studies showed that mTNF-α+ M2 macrophages were more potent in inducing Treg differentiation and proliferation than their mTNF-α- counterparts, whereas the effects of mTNF-α+ M2 macrophages were largely reversed by separation of M2 macrophages using a transwell or TNFR2-blocking Ab in the culture. Finally, PF also promoted in vitro Treg generation induced by M2 macrophages. Thus, we demonstrated that mTNFα-TNFR2 interaction is a new mechanism responsible for Treg differentiation mediated by M2 macrophages. We provided the first evidence that PF may be used to treat lupus nephritis. Copyright © 2021. Published by Elsevier Inc.

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出版当年[2020]版:
大类 | 2 区 医学
小类 | 1 区 药学
最新[2025]版:
大类 | 2 区 医学
小类 | 2 区 药学
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出版当年[2019]版:
Q1 PHARMACOLOGY & PHARMACY
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Q1 PHARMACOLOGY & PHARMACY

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第一作者机构: [1]Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, and the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China
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通讯机构: [1]Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, and the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510006, China [*1]Section of Immunology & Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, 55 Nei Huan Xi Lu, College Town, Guangzhou, Guangdong 510006, China.
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