CoChat
Sign Up
Cited by 149Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesEstrogen and related hormone effects

Targeting estrogen receptor β in microglia and T cells to treat experimental autoimmune encephalomyelitis

Open access
Wu, Wan-fu, Tan, Xin-jie, Dai, Yu-bing, Krishnan, Venkatesh, Warner, Margaret, Gustafsson, Jan-Åke·2013·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1300313110PMC PMC3587193
Open this paper in CoChat — free account

Abstract

A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to defective neurons. Although estrogen can inactivate microglia and inhibit the recruitment of T cells and macrophages into the CNS, there is controversy regarding which of the two estrogen receptors (ERs), ERα or ERβ, mediates the beneficial effects in microglia. In this study, we found that ERβ, but not ERα, is expressed in microglia. Using the experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice, we evaluated the benefit of an ERβ agonist as a modulator of neuroinflammation. Treatment of EAE mice with LY3201, a selective ERβ agonist provided by Eli Lilly, resulted in marked reduction of activated microglia in the spinal cord. LY3201 down-regulated the nuclear transcription factor NF - κB, as well as the NF-κB–induced gene inducible nitric oxide synthase in microglia and CD3 + T cells. In addition, LY3201 inhibited T-cell reactivity through regulation of indoleamine-2,3-dioxygenase. In the EAE model, treatment with LY3201 decreased mortality in the first 2 wk after disease onset, and also reduced the severity of symptoms in mice surviving for 4 wk. Our data show that ERβ-selective agonists, by modulating the immune system in both microglia and T cells, offer promise as a useful class of drugs for treating degenerative diseases of the CNS.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1300313110

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Microglia can express receptors for ovarian hormones such as estradiol, and for testicular hormones like testosterone.

    “Notably, microglia can express receptors for ovarian hormones such as estradiol, and for testicular hormones like testosterone [35–37].”

    From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [37]

    The Results section (page not provided) reports that mouse microglia express estrogen receptor β, supporting the estradiol-receptor part of the claim. The passages retrieved for testosterone and androgen receptors do not establish that microglia express receptors for testicular hormones, so this source supports only part of the sentence. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 43

  1. [1]Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000;343(13):938–952. doi: 10.1056/NEJM200009283431307. [DOI] [PubMed] [Google Scholar] · DOI
  2. [2]Dyment DA, Ebers GC, Sadovnick AD. Genetics of multiple sclerosis. Lancet Neurol. 2004;3(2):104–110. doi: 10.1016/s1474-4422(03)00663-x. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  3. [3]Vukusic S, Confavreux C. Primary and secondary progressive multiple sclerosis. J Neurol Sci. 2003;206(2):153–155. doi: 10.1016/s0022-510x(02)00427-6. [DOI] [PubMed] [Google Scholar] · DOI
  4. [4]Wingerchuk DM. Current evidence and therapeutic strategies for multiple sclerosis. Semin Neurol. 2008;28(1):56–68. doi: 10.1055/s-2007-1019128. [DOI] [PubMed] [Google Scholar] · DOI
  5. [5]Wolinsky JS, et al. PROMiSe Trial Study Group Glatiramer acetate in primary progressive multiple sclerosis: Results of a multinational, multicenter, double-blind, placebo-controlled trial. Ann Neurol. 2007;61(1):14–24. doi: 10.1002/ana.21079. [DOI] [PubMed] [Google Scholar] · DOI
  6. [6]Hartung HP, et al. Mitoxantrone in Multiple Sclerosis Study Group (MIMS) Mitoxantrone in progressive multiple sclerosis: A placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360(9350):2018–2025. doi: 10.1016/S0140-6736(02)12023-X. [DOI] [PubMed] [Google Scholar] · DOI
  7. [7]Polman CH, et al. AFFIRM Investigators A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910. doi: 10.1056/NEJMoa044397. [DOI] [PubMed] [Google Scholar] · DOI
  8. [8]Rice GP, Hartung HP, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: Mechanisms and rationale. Neurology. 2005;64(8):1336–1342. doi: 10.1212/01.WNL.0000158329.30470.D0. [DOI] [PubMed] [Google Scholar] · DOI
  9. [9]Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms underlying inflammation in neurodegeneration. Cell. 2010;140(6):918–934. doi: 10.1016/j.cell.2010.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI · Paper page
  10. [11]Streit WJ. Microglia as neuroprotective, immunocompetent cells of the CNS. Glia. 2002;40(2):133–139. doi: 10.1002/glia.10154. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  11. [14]Benveniste EN. Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis. J Mol Med (Berl) 1997;75(3):165–173. doi: 10.1007/s001090050101. [DOI] [PubMed] [Google Scholar] · DOI
  12. [15]Ratchford JN, et al. Decreased microglial activation in MS patients treated with glatiramer acetate. J Neurol. 2012;259(6):1199–1205. doi: 10.1007/s00415-011-6337-x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  13. [16]Gold SM, et al. Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERalpha) Lab Invest. 2009;89(10):1076–1083. doi: 10.1038/labinvest.2009.79. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  14. [17]Saijo K, Collier JG, Li AC, Katzenellenbogen JA, Glass CK. An ADIOL-ERβ-CtBP transrepression pathway negatively regulates microglia-mediated inflammation. Cell. 2011;145(4):584–595. doi: 10.1016/j.cell.2011.03.050. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  15. [18]Chadwick CC, et al. Identification of pathway-selective estrogen receptor ligands that inhibit NF-kappaB transcriptional activity. Proc Natl Acad Sci USA. 2005;102(7):2543–2548. doi: 10.1073/pnas.0405841102. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  16. [19]Baker AE, Brautigam VM, Watters JJ. Estrogen modulates microglial inflammatory mediator production via interactions with estrogen receptor beta. Endocrinology. 2004;145(11):5021–5032. doi: 10.1210/en.2004-0619. [DOI] [PubMed] [Google Scholar] · DOI
  17. [20]Vegeto E, et al. The endogenous estrogen status regulates microglia reactivity in animal models of neuroinflammation. Endocrinology. 2006;147(5):2263–2272. doi: 10.1210/en.2005-1330. [DOI] [PubMed] [Google Scholar] · DOI
  18. [22]Karin M, Greten FR. NF-kappaB: Linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–759. doi: 10.1038/nri1703. [DOI] [PubMed] [Google Scholar] · DOI
  19. [23]Baeuerle PA, Baltimore D. NF-kappa B: Ten years after. Cell. 1996;87(1):13–20. doi: 10.1016/s0092-8674(00)81318-5. [DOI] [PubMed] [Google Scholar] · DOI
  20. [24]van Loo G, et al. Inhibition of transcription factor NF-kappaB in the central nervous system ameliorates autoimmune encephalomyelitis in mice. Nat Immunol. 2006;7(9):954–961. doi: 10.1038/ni1372. [DOI] [PubMed] [Google Scholar] · DOI
  21. [25]Ousman SS, et al. Protective and therapeutic role for alphaB-crystallin in autoimmune demyelination. Nature. 2007;448(7152):474–479. doi: 10.1038/nature05935. [DOI] [PubMed] [Google Scholar] · DOI
  22. [26]Willenborg DO, Staykova M, Fordham S, O’Brien N, Linares D. The contribution of nitric oxide and interferon gamma to the regulation of the neuro-inflammation in experimental autoimmune encephalomyelitis. J Neuroimmunol. 2007;191(1-2):16–25. doi: 10.1016/j.jneuroim.2007.09.007. [DOI] [PubMed] [Google Scholar] · DOI
  23. [27]Pautz A, et al. Regulation of the expression of inducible nitric oxide synthase. Nitric Oxide. 2010;23(2):75–93. doi: 10.1016/j.niox.2010.04.007. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  24. [28]Hooper DC, et al. Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: Implications for the treatment of multiple sclerosis. Proc Natl Acad Sci USA. 1997;94(6):2528–2533. doi: 10.1073/pnas.94.6.2528. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  25. [29]Graeber MB, Streit WJ. Microglia: Biology and pathology. Acta Neuropathol. 2010;119(1):89–105. doi: 10.1007/s00401-009-0622-0. [DOI] [PubMed] [Google Scholar] · DOI
  26. [30]Koning N, Bö L, Hoek RM, Huitinga I. Downregulation of macrophage inhibitory molecules in multiple sclerosis lesions. Ann Neurol. 2007;62(5):504–514. doi: 10.1002/ana.21220. [DOI] [PubMed] [Google Scholar] · DOI
  27. [31]Qian L, Flood PM, Hong JS. Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm. 2010;117(8):971–979. doi: 10.1007/s00702-010-0428-1. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  28. [32]Schieven GL. The biology of p38 kinase: A central role in inflammation. Curr Top Med Chem. 2005;5(10):921–928. doi: 10.2174/1568026054985902. [DOI] [PubMed] [Google Scholar] · DOI
  29. [33]Tyree CM, Zou A, Allegretto EA. 17beta-Estradiol inhibits cytokine induction of the human E-selectin promoter. J Steroid Biochem Mol Biol. 2002;80(3):291–297. doi: 10.1016/s0960-0760(02)00022-5. [DOI] [PubMed] [Google Scholar] · DOI
  30. [34]Valentine JE, Kalkhoven E, White R, Hoare S, Parker MG. Mutations in the estrogen receptor ligand binding domain discriminate between hormone-dependent transactivation and transrepression. J Biol Chem. 2000;275(33):25322–25329. doi: 10.1074/jbc.M002497200. [DOI] [PubMed] [Google Scholar] · DOI
  31. [35]Kröncke KD, Fehsel K, Kolb-Bachofen V. Inducible nitric oxide synthase in human diseases. Clin Exp Immunol. 1998;113(2):147–156. doi: 10.1046/j.1365-2249.1998.00648.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  32. [36]Mankan AK, Lawless MW, Gray SG, Kelleher D, McManus R. NF-kappaB regulation: The nuclear response. J Cell Mol Med. 2009;13(4):631–643. doi: 10.1111/j.1582-4934.2009.00632.x. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  33. [39]Komi J, Lassila O. Nonsteroidal anti-estrogens inhibit the functional differentiation of human monocyte-derived dendritic cells. Blood. 2000;95(9):2875–2882. [PubMed] [Google Scholar]
  34. [40]Richardson TI, et al. Benzopyrans as selective estrogen receptor beta agonists (SERBAs), part 3: Synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification. Bioorg Med Chem Lett. 2007;17(17):4824–4828. doi: 10.1016/j.bmcl.2007.06.052. [DOI] [PubMed] [Google Scholar] · DOI
  35. [41]Tan XJ, Dai YB, Wu WF, Warner M, Gustafsson JÅ. Anxiety in liver X receptor β knockout female mice with loss of glutamic acid decarboxylase in ventromedial prefrontal cortex. Proc Natl Acad Sci USA. 2012;109(19):7493–7498. doi: 10.1073/pnas.1205189109. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  36. [42]Dai YB, Tan XJ, Wu WF, Warner M, Gustafsson JA. Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease. Proc Natl Acad Sci USA. 2012;109:13112–13117. doi: 10.1073/pnas.1210833109. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  37. [43]Tan XJ, et al. Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand. Proc Natl Acad Sci USA. 2012;109(5):1708–1712. doi: 10.1073/pnas.1121162109. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  38. [44]Suzuki H, et al. Involvement of estrogen receptor β in maintenance of serotonergic neurons of the dorsal raphe. Mol Psychiatry. 2012 doi: 10.1038/mp.2012.62. [DOI] [PubMed] [Google Scholar] · DOI
  39. [45]Sugiyama N, et al. Spatiotemporal dynamics of the expression of estrogen receptors in the postnatal mouse brain. Mol Psychiatry. 2009;14(2):223–232, 117. doi: 10.1038/mp.2008.118. [DOI] [PubMed] [Google Scholar] · DOI
  40. [46]Fan X, Warner M, Gustafsson JA. Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons. Proc Natl Acad Sci USA. 2006;103(51):19338–19343. doi: 10.1073/pnas.0609663103. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  41. [47]Fan X, Kim HJ, Warner M, Gustafsson JA. Estrogen receptor beta is essential for sprouting of nociceptive primary afferents and for morphogenesis and maintenance of the dorsal horn interneurons. Proc Natl Acad Sci USA. 2007;104(34):13696–13701. doi: 10.1073/pnas.0705936104. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  42. [48]Esslimani-Sahla M, et al. Increased estrogen receptor betacx expression during mammary carcinogenesis. Clin Cancer Res. 2005;11(9):3170–3174. doi: 10.1158/1078-0432.CCR-04-2298. [DOI] [PubMed] [Google Scholar] · DOI
  43. [49]Muthusamy S, et al. Estrogen receptor β and 17β-hydroxysteroid dehydrogenase type 6, a growth regulatory pathway that is lost in prostate cancer. Proc Natl Acad Sci USA. 2011;108(50):20090–20094. doi: 10.1073/pnas.1117772108. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Authors
Wu, W.-F., Tan, X.-J., Dai, Y.-B., Krishnan, V., Warner, M., & Gustafsson, J.-Å.
Affiliations
  • Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX 77204;
  • Eli Lilly (United States) (US)
  • University of Houston (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2013-02-11
Volume
110
Issue
9
Pages
3543-3548
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1300313110
PMC
PMC3587193
OpenAlex
W2075811276
Cited by
149
References
6
Citations by year
2026: 8 · 2025: 7 · 2024: 7 · 2023: 5 · 2022: 5 · 2021: 9 · 2020: 15 · 2019: 12 · 2018: 9 · 2017: 10 · 2016: 22 · 2015: 12 · 2014: 20 · 2013: 7
FWCI
11.41
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
estrogen receptor beta, experimental autoimmune encephalomyelitis, microglia, T cells, neuroinflammation, estrogen receptor agonists, NF-κB, indoleamine 2,3-dioxygenase, nitric oxide synthase, multiple sclerosis, neurodegenerative diseases
MeSH terms
Animals, Benzopyrans, Encephalomyelitis, Autoimmune, Experimental, Female, Spinal Cord, T-Lymphocytes, Down-Regulation, NF-kappa B, Microglia, Estrogen Receptor alpha, Estrogen Receptor beta, Indoleamine-Pyrrole 2,3,-Dioxygenase, Mice, Nitric Oxide Synthase Type II, Molecular Targeted Therapy

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review