{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T23:28:04Z","timestamp":1793402884946,"version":"4.5.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T00:00:00Z","timestamp":1625443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Macrophages, a major subset of innate immune cells, are main infiltrating cells in the kidney in lupus nephritis. Macrophages with different phenotypes exert diverse or even opposite effects on the development of lupus nephritis. Substantial evidence has shown that macrophage M2 polarization is beneficial to individuals with chronic kidney disease. Further, it has been reported that PD-1 ligands (PD-Ls) contribute to M2 polarization of macrophages and their immunosuppressive effects. Total glucosides of paeony (TGP), originally extracted from Radix Paeoniae Alba, has been approved in China to treat some autoimmune diseases. Here, we investigated the potentially therapeutic effects of TGP on lupus nephritis in a pristane-induced murine model and explored the molecular mechanisms regulating macrophage phenotypes. We found that TGP treatment significantly improved renal function by decreasing the urinary protein and serum creatinine, reducing serum anti-ds-DNA level and ameliorating renal immunopathology. TGP increased the frequency of splenic and peritoneal F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    CD11b\n                    <jats:sup>+<\/jats:sup>\n                    CD206\n                    <jats:sup>+<\/jats:sup>\n                    M2-like macrophages with no any significant effect on F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    CD11b\n                    <jats:sup>+<\/jats:sup>\n                    CD86\n                    <jats:sup>+<\/jats:sup>\n                    M1-like macrophages. Immunofluorescence double-stainings of the renal tissue showed that TGP treatment increased the frequency of F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    Arg1\n                    <jats:sup>+<\/jats:sup>\n                    subset while decreasing the percentage of F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    iNOS\n                    <jats:sup>+<\/jats:sup>\n                    subset. Importantly, TGP treatment increased the percentage of both F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    CD11b\n                    <jats:sup>+<\/jats:sup>\n                    PD-L1\n                    <jats:sup>+<\/jats:sup>\n                    and F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    CD11b\n                    <jats:sup>+<\/jats:sup>\n                    PD-L2\n                    <jats:sup>+<\/jats:sup>\n                    subsets in spleen and peritoneal lavage fluid as well as the kidney. Furthermore, TGP augmented the expressions of CD206, PD-L2 and phosphorylated STAT6 in IL-4-treated Raw264.7 macrophages\n                    <jats:italic>in vitro<\/jats:italic>\n                    while its effects on PD-L2 were abolished by pretreatment of the cells with an inhibitor of STAT6, AS1517499. However, TGP treatment did not affect the expressions of STAT1 and PD-L1 in Raw264.7 macrophages treated with LPS\/IFN-\u03b3\n                    <jats:italic>in vitro<\/jats:italic>\n                    , indicating a possibly indirect effect of TGP on PD-L1 expression on macrophages\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Thus, for the first time, we demonstrated that TGP may be a potent drug to treat lupus nephritis by inducing F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    CD11b\n                    <jats:sup>+<\/jats:sup>\n                    CD206\n                    <jats:sup>+<\/jats:sup>\n                    and F4\/80\n                    <jats:sup>+<\/jats:sup>\n                    CD11b\n                    <jats:sup>+<\/jats:sup>\n                    PD-L2\n                    <jats:sup>+<\/jats:sup>\n                    macrophages through IL-4\/STAT6\/PD-L2 signaling pathway.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2021.683249","type":"journal-article","created":{"date-parts":[[2021,7,5]],"date-time":"2021-07-05T11:02:47Z","timestamp":1625482967000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":67,"title":["Total Glucosides of Paeony Ameliorate Pristane-Induced Lupus Nephritis by Inducing PD-1 ligands+ Macrophages via Activating IL-4\/STAT6\/PD-L2 Signaling"],"prefix":"10.3389","volume":"12","author":[{"given":"Chun-Ling","family":"Liang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxuan","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huazhen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qunfang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuan-Jian","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39594","article-title":"Risk of End-Stage Renal Disease in Patients With Lupus Nephritis, 1971-2015: A Systematic Review and Bayesian Meta-Analysis","volume":"68","author":"Tektonidou","year":"2016","journal-title":"Arthritis Rheumatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2177\/jsci.38.135","article-title":"The Pathogenic Role of Macrophage in Lupus Nephritis","volume":"38","author":"Sugiyama","year":"2015","journal-title":"Nihon Rinsho Meneki Gakkai Kaishi"},{"key":"B3","article-title":"Therapeutic Targeting of Macrophages in Lupus Nephritis","volume":"20","author":"Chalmers","year":"2015","journal-title":"Discov Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41581-019-0110-2","article-title":"Macrophages: Versatile Players in Renal Inflammation and Fibrosis","volume":"15","author":"Tang","year":"2019","journal-title":"Nat Rev Nephrol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.27450","article-title":"Active Vitamin D Regulates Macrophage M1\/M2 Phenotypes Via the STAT-1-TREM-1 Pathway in Diabetic Nephropathy","volume":"234","author":"Zhang","year":"2019","journal-title":"J Cell Physiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.132826","article-title":"Mitophagy-Dependent Macrophage Reprogramming Protects Against Kidney Fibrosis","volume":"4","author":"Bhatia","year":"2019","journal-title":"JCI Insight"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2018.05.007","article-title":"Quercetin Ameliorates Kidney Injury and Fibrosis by Modulating M1\/M2 Macrophage Polarization","volume":"154","author":"Lu","year":"2018","journal-title":"Biochem Pharmacol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1159\/000431214","article-title":"Macrophage Phenotype in Kidney Injury and Repair","volume":"1","author":"Meng","year":"2015","journal-title":"Kidney Dis (Basel)"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.574491","article-title":"Programmed Cell Death Ligand (PD-L)-1 Contributes to the Regulation of CD4(+) T Effector and Regulatory T Cells in Cutaneous Leishmaniasis","volume":"11","author":"de Freitas","year":"2020","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/srep38362","article-title":"PD-1\/PD-L Pathway Inhibits M.tb-specific CD4(+) T-Cell Functions and Phagocytosis of Macrophages in Active Tuberculosis","volume":"6","author":"Shen","year":"2016","journal-title":"Sci Rep"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-271981","article-title":"Alternatively Activated Macrophages Inhibit T-Cell Proliferation by Stat6-Dependent Expression of PD-L2","volume":"116","author":"Huber","year":"2010","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201141947","article-title":"IL-33 Attenuates EAE by Suppressing IL-17 and IFN-Gamma Production and Inducing Alternatively Activated Macrophages","volume":"42","author":"Jiang","year":"2012","journal-title":"Eur J Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1071\/fp18080","article-title":"The Effects of Total Glucosides of Paeony (TGP) and Paeoniflorin (Pae) on Inflammatory-Immune Responses in Rheumatoid Arthritis (RA)","volume":"46","author":"Zhang","year":"2019","journal-title":"Funct Plant Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2019.00204","article-title":"Dynamic Alterations in the Gut Microbiota of Collagen-Induced Arthritis Rats Following the Prolonged Administration of Total Glucosides of Paeony","volume":"9","author":"Peng","year":"2019","journal-title":"Front Cell Infect Microbiol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1684\/ejd.2016.2946","article-title":"Efficacy and Safety of Total Glucosides of Paeony Combined With Acitretin in the Treatment of Moderate-to-Severe Plaque Psoriasis: A Double-Blind, Randomised, Placebo-Controlled 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Upregulation of PD-L1 Expression in Pancreatic Cancer Cell Lines","volume":"37","author":"Doi","year":"2017","journal-title":"Oncol Rep"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0931259100","article-title":"PD-L1 and PD-L2 are Differentially Regulated by Th1 and Th2 Cells","volume":"100","author":"Loke","year":"2003","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Frontiers in 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