CoChat
Sign Up
Cited by 57Neuroinflammation and Neurodegeneration MechanismsEstrogen and related hormone effectsPhagocytosis and Immune Regulation

Estrogen Promotes Pro-resolving Microglial Behavior and Phagocytic Cell Clearance Through the Actions of Annexin A1

Open access
Loiola, Rodrigo Azevedo, Wickstead, Edward S., Solito, Egle, McArthur, Simon·2019·Frontiers in Endocrinology
DOI 10.3389/fendo.2019.00420PMC PMC6607409

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Local production of estrogen rapidly follows brain tissue injury, but the role this hormone plays in regulating the response to neural damage or in the modulation of mediators regulating inflammation is in many ways unclear. Using the murine BV2 microglia model as well as primary microglia from wild-type and annexin A1 (AnxA1) null mice, we have identified two related mechanisms whereby estradiol can modulate microglial behavior in a receptor specific fashion. Firstly, estradiol, via estrogen receptor β (ERβ), enhanced the phagocytic clearance of apoptotic cells, acting through increased production and release of the protein AnxA1. Secondly, stimulation of either ERβ or the G protein coupled estrogen receptor GPER promoted the adoption of an anti-inflammatory/pro-resolving phenotype, an action similarly mediated through AnxA1. Together, these data suggest the hypothesis that locally produced estrogen acts through AnxA1 to exert powerful pro-resolving actions, controlling and limiting brain inflammation and ultimately protecting this highly vulnerable organ. Given the high degree of receptor selectivity in evoking these responses, we suggest that the use of selective estrogen receptor ligands may hold therapeutic promise in the treatment of neuroinflammation, avoiding unwanted generalized effects.

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 · 10.3389/fendo.2019.00420

Cites

5 of 5 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?

  • Sex differences extend to individual cells within the brain parenchyma, including microglia.

    “Sex differences also extend to individual cells within the brain parenchyma, including microglia [3, 14, 15].”

    From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [15]

    The Discussion (page unavailable) describes sex differences in CNS inflammatory diseases and reports that estrogen modulates microglial behavior. That supports a sex-hormone effect at the cellular level, but the paper does not establish a difference between male and female microglia; its primary microglial cultures came from female mice only (Materials and Methods, page unavailable). (LLM, conf=0.82)

    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: 57

  1. [1]Gillies GE McArthur S. Independent influences of sex steroids of systemic and central origin in a rat model of Parkinson's disease: a contribution to sex-specific neuroprotection by estrogens. Horm Behav. (2010) 57: 23– 34. 10.1016/j.yhbeh.2009.06.002 19538962 · DOI
  2. [2]Nadkarni S McArthur S. Oestrogen and immunomodulation: New mechanisms that impact on peripheral and central immunity. Curr Opin Pharmacol. (2013) 13: 576– 81. 10.1016/j.coph.2013.05.007 23731522 · DOI
  3. [3]Johann S Beyer C. Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia. J Steroid Biochem Mol Biol. (2013) 137: 71– 81. 10.1016/j.jsbmb.2012.11.006 23196064 · DOI
  4. [4]Duncan KA Saldanha CJ. Neuroinflammation induces glial aromatase expression in the uninjured songbird brain. J Neuroinflammation. (2011) 8: 81. 10.1186/1742-2094-8-81 21767382 PMC3158750 · DOI
  5. [5]Azcoitia I Sierra A Veiga S Honda S Harada N Garcia-Segura LM. Brain aromatase is neuroprotective. J Neurobiol. (2001) 47: 318– 29. 10.1002/neu.1038 11351342 · DOI
  6. [6]Ren Y Savill J. Apoptosis: the importance of being eaten. Cell Death Differ. (1998) 5: 563– 8. 10.1038/sj.cdd.4400407 10200510 · DOI
  7. [7]Vegeto E Pollio G Ciana P Maggi A. Estrogen blocks inducible nitric oxide synthase accumulation in LPS-activated microglia cells. Exp Gerontol. (2000) 35: 1309– 16. 10.1016/S0531-5565(00)00161-3 11113609 · DOI
  8. [8]Bruce-Keller AJ Keeling JL Keller JN Huang FF Camondola S Mattson MP. Antiinflammatory effects of estrogen on microglial activation. Endocrinology. (2000) 141: 3646– 56. 10.1210/endo.141.10.7693 11014219 · DOI
  9. [9]Vegeto E Bonincontro C Pollio G Sala A Viappiani S Nardi F. Estrogen prevents the lipopolysaccharide-induced inflammatory response in microglia. J Neurosci. (2001) 21: 1809– 18. 10.1523/JNEUROSCI.21-06-01809.2001 11245665 PMC6762610 · DOI
  10. [10]Dimayuga FO Reed JL Carnero GA Wang C Dimayuga ER Dimayuga VM. Estrogen and brain inflammation: effects on microglial expression of MHC, costimulatory molecules and cytokines. J Neuroimmunol. (2005) 161: 123– 36. 10.1016/j.jneuroim.2004.12.016 15748951 · DOI
  11. [12]Faustino JV Wang X Johnson CE Klibanov A Derugin N Wendland MF. Microglial cells contribute to endogenous brain defenses after acute neonatal focal stroke. J Neurosci. (2011) 31: 12992– 3001. 10.1523/JNEUROSCI.2102-11.2011 21900578 PMC3539822 · DOI
  12. [13]Montero M González B Zimmer J. Immunotoxic depletion of microglia in mouse hippocampal slice cultures enhances ischemia-like neurodegeneration. Brain Res. (2009) 1291: 140– 52. 10.1016/j.brainres.2009.06.097 19595678 · DOI
  13. [14]Fullerton JN Gilroy DW. Resolution of inflammation: a new therapeutic frontier. Nat Rev Drug Discov. (2016) 15: 551– 67. 10.1038/nrd.2016.39 27020098 · DOI · Paper page
  14. [15]Lim LH Solito E Russo-Marie F Flower RJ Perretti M. Promoting detachment of neutrophils adherent to murine postcapillary venules to control inflammation: effect of lipocortin 1. Proc Natl Acad Sci USA. (1998) 95: 14535– 9. 10.1073/pnas.95.24.14535 9826735 PMC24408 · DOI
  15. [16]Vago JP Nogueira CR Tavares LP Soriani FM Lopes F Russo RC. Annexin A1 modulates natural and glucocorticoid-induced resolution of inflammation by enhancing neutrophil apoptosis. J Leukoc Biol. (2012) 92: 249– 58. 10.1189/jlb.0112008 22493082 · DOI
  16. [17]McArthur S Gobbetti T Kusters DHM Reutelingsperger CP Flower RJ Perretti M. Definition of a novel pathway centered on lysophosphatidic acid to recruit monocytes during the resolution phase of tissue inflammation. J Immunol. (2015) 195: 1500733. 10.4049/jimmunol.1500733 26101324 PMC4505961 · DOI
  17. [18]Gobbetti T Coldewey SM Chen J McArthur S Le Faouder P Cenac N. Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis. Proc Natl Acad Sci USA. (2014) 111: 18685– 90. 10.1073/pnas.1410938111 25512512 PMC4284560 · DOI
  18. [19]Scannell M Flanagan MB deStefani A Wynne KJ Cagney G Godson C. Annexin-1 and peptide derivatives are released by apoptotic cells and stimulate phagocytosis of apoptotic neutrophils by macrophages. J Immunol. (2007) 178: 4595– 605. 10.4049/jimmunol.178.7.4595 17372018 · DOI
  19. [20]Cristante E McArthur S Mauro C Maggioli E Romero IA Wylezinska-Arridge M. Identification of an essential endogenous regulator of blood-brain barrier integrity, and its pathological and therapeutic implications. Proc Natl Acad Sci USA. (2013) 110: 832– 41. 10.1073/pnas.1209362110 23277546 PMC3549094 · DOI
  20. [21]McArthur S Cristante E Paterno M Christian H Roncaroli F Gillies GE. Annexin A1: a central player in the anti-inflammatory and neuroprotective role of microglia. J Immunol. (2010) 185: 6317– 28. 10.4049/jimmunol.1001095 20962261 PMC3145124 · DOI
  21. [22]Nadkarni S Cooper D Brancaleone V Bena S Perretti M. Activation of the annexin A1 pathway underlies the protective effects exerted by estrogen in polymorphonuclear leukocytes. Arterioscler Thromb Vasc Biol. (2011) 31: 2749– 59. 10.1161/ATVBAHA.111.235176 21836070 PMC3357483 · DOI
  22. [23]Davies E Omer S Morris JF Christian HC. The influence of 17beta-estradiol on annexin 1 expression in the anterior pituitary of the female rat and in a folliculo-stellate cell line. J Endocrinol. (2007) 192: 429– 42. 10.1677/JOE-06-0132 17283243 PMC1994562 · DOI
  23. [24]Hughes EL Cover PO Buckingham JC Gavins FNE. Role and interactions of annexin A1 and oestrogens in the manifestation of sexual dimorphisms in cerebral and systemic inflammation. Br J Pharmacol. (2013) 169: 539– 53. 10.1111/j.1476-5381.2012.02146.x 22897118 PMC3682703 · DOI
  24. [25]Blasi E Barluzzi R Bocchini V Mazzolla R Bistoni F. Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol. (1990) 27: 229– 37. 10.1016/0165-5728(90)90073-V 2110186 · DOI
  25. [26]Hannon R Croxtall JD Getting SJ Roviezzo F Yona S Paul-Clark MJ Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse. FASEB J. (2003) 17: 253– 5. 10.1096/fj.02-0239fje 12475898 · DOI
  26. [27]De Haas AH Boddeke HWGM Biber K. Region-specific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia. (2008) 56: 888– 94. 10.1002/glia.20663 18338796 · DOI
  27. [28]Green LC Wagner DA Glogowski J Skipper PL Wishnok JS Tannenbaum SR Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem. (1982) 126: 131– 8. 10.1016/0003-2697(82)90118-X 7181105 · DOI
  28. [29]Maggioli E McArthur S Mauro C Kieswich J Kusters DH Reutelingsperger CP. Estrogen protects the blood-brain barrier from inflammation-induced disruption and increased lymphocyte trafficking. Brain Behav Immun. (2015) 51: 212– 22. 10.1016/j.bbi.2015.08.020 26321046 · DOI
  29. [30]Sureda FX Junyent F Verdaguer E Auladell C Pelegri C Vilaplana J. Antiapoptotic drugs: a therapautic strategy for the prevention of neurodegenerative diseases. Curr Pharm Des. (2011) 17: 230– 45. 10.2174/138161211795049732 21348832 · DOI
  30. [31]Neher JJ Neniskyte U Brown GC. Primary phagocytosis of neurons by inflamed microglia: potential roles in neurodegeneration. Front Pharmacol. (2012) 3: 27. 10.3389/fphar.2012.00027 22403545 PMC3288722 · DOI
  31. [33]Nowak K Jabłońska E Ratajczak-Wrona W. Neutrophils life under estrogenic and xenoestrogenic control. J Steroid Biochem Mol Biol. (2019) 186: 203– 11. 10.1016/j.jsbmb.2018.10.015 30381249 · DOI
  32. [34]Jurado-Coronel JC Cabezas R Ávila Rodríguez MF Echeverria V García-Segura LM Barreto GE. Sex differences in Parkinson's disease: features on clinical symptoms, treatment outcome, sexual hormones and genetics. Front Neuroendocrinol. (2018) 50: 18– 30. 10.1016/j.yfrne.2017.09.002 28974386 · DOI · Paper page
  33. [35]Ferretti MT Iulita MF Cavedo E Chiesa PA Schumacher Dimech A Santuccione Chadha A. Sex differences in Alzheimer disease—the gateway to precision medicine. Nat Rev Neurol. (2018) 14: 457– 69. 10.1038/s41582-018-0032-9 29985474 · DOI · Paper page
  34. [36]Habib P Beyer C. Regulation of brain microglia by female gonadal steroids. J Steroid Biochem Mol Biol. (2015) 146: 3– 14. 10.1016/j.jsbmb.2014.02.018 24607811 · DOI · Paper page
  35. [38]Engler-Chiurazzi EB Brown CM Povroznik JM Simpkins JW. Estrogens as neuroprotectants: estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol. (2017) 157: 188– 211. 10.1016/j.pneurobio.2015.12.008 26891883 PMC4985492 · DOI
  36. [41]Villa A Vegeto E Poletti A Maggi A. Estrogens, neuroinflammation and neurodegeneration. Endocr Rev. (2016) 37: 372– 402. 10.1210/er.2016-1007 27196727 PMC4971309 · DOI · Paper page
  37. [42]Sachet M Liang YY Oehler R. The immune response to secondary necrotic cells. Apoptosis. (2017) 22: 1189– 204. 10.1007/s10495-017-1413-z 28861714 PMC5630647 · DOI · Paper page
  38. [43]Vilalta A Brown GC. Neurophagy, the phagocytosis of live neurons and synapses by glia, contributes to brain development and disease. FEBS J. (2018) 285: 3566– 75. 10.1111/febs.14323 29125686 · DOI
  39. [44]Yu W Zheng H Lin W Tajima A Zhang Y Zhang X. Estrogen promotes Leydig cell engulfment by macrophages in male infertility. J Clin Invest. (2014) 124: 2709– 21. 10.1172/JCI59901 24762434 PMC4038558 · DOI
  40. [45]Ribas V Drew BG Le JA Soleymani T Daraei P Sitz D. Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Natl Acad Sci USA. (2011) 108: 16457– 62. 10.1073/pnas.1104533108 21900603 PMC3182726 · DOI
  41. [46]Guan J Yang B Fan Y Zhang J. GPER Agonist G1 attenuates neuroinflammation and dopaminergic neurodegeneration in Parkinson disease. Neuroimmunomodulation. (2017) 24: 60– 6. 10.1159/000478908 28810246 · DOI
  42. [47]Pan M-X Tang J-C Liu R Feng Y-G Wan Q. Effects of estrogen receptor GPR30 agonist G1 on neuronal apoptosis and microglia polarization in traumatic brain injury rats. Chin J Traumatol. (2018) 21: 224– 8. 10.1016/j.cjtee.2018.04.003 30017543 PMC6085194 · DOI
  43. [48]Zhang Z Qin P Deng Y Ma Z Guo H Guo H. The novel estrogenic receptor GPR30 alleviates ischemic injury by inhibiting TLR4-mediated microglial inflammation. J Neuroinflammation. (2018) 15: 206. 10.1186/s12974-018-1246-x 30001721 PMC6043971 · DOI
  44. [49]Zhao T-Z Ding Q Hu J He S-M Shi F Ma L-T. GPER expressed on microglia mediates the anti-inflammatory effect of estradiol in ischemic stroke. Brain Behav. (2016) 6: e00449. 10.1002/brb3.449 27127723 PMC4840664 · DOI
  45. [50]Solito E McArthur S Christian H Gavins F Buckingham JC Gillies GE. Annexin A1 in the brain–undiscovered roles? Trends Pharmacol Sci. (2008) 29: 135– 42. 10.1016/j.tips.2007.12.003 18262660 · DOI
  46. [51]Zhong YH Dhawan J Kovoor JA Sullivan J Zhang WX Choi D. Aromatase and neuroinflammation in rat focal brain ischemia. J Steroid Biochem Mol Biol. (2017) 174: 225– 33. 10.1016/j.jsbmb.2017.09.019 28964927 · DOI
  47. [52]Ghorbanpoor S Garcia-Segura LM Haeri-Rohani A Khodagholi F Jorjani M. Aromatase inhibition exacerbates pain and reactive gliosis in the dorsal horn of the spinal cord of female rats caused by spinothalamic tract injury. Endocrinology. (2014) 155: 4341– 55. 10.1210/en.2014-1158 25105782 · DOI
  48. [53]Eggen BJL Raj D Hanisch U-K Boddeke HWGM. Microglial phenotype and adaptation. J Neuroimmune Pharmacol. (2013) 8: 807– 23. 10.1007/s11481-013-9490-4 23881706 · DOI
  49. [54]Xu L He D Bai Y. Microglia-mediated inflammation and neurodegenerative disease. Mol Neurobiol. (2016) 53: 6709– 15. 10.1007/s12035-015-9593-4 26659872 · DOI
  50. [55]Céspedes Rubio ÁE Pérez-Alvarez MJ Lapuente Chala C Wandosell F. Sex steroid hormones as neuroprotective elements in ischemia models. J Endocrinol. (2018) 237: R65– 81. 10.1530/JOE-18-0129 29654072 · DOI
  51. [56]Akabori H Moeinpour F Bland KI Chaudry IH. Mechanism of the anti-inflammatory effect Of 17beta-estradiol on brain following trauma-hemorrhage. Shock. (2010) 33: 43– 8. 10.1097/SHK.0b013e3181b0ebcb 19536048 · DOI
  52. [57]Sárvári M Hrabovszky E Kalló I Solymosi N Tóth K Likó I. Estrogens regulate neuroinflammatory genes via estrogen receptors α and β in the frontal cortex of middle-aged female rats. J Neuroinflammation. (2011) 8: 82. 10.1186/1742-2094-8-82 21774811 PMC3161870 · DOI
  53. [58]Smith JA Das A Butler JT Ray SK Banik NL Estrogen or estrogen receptor agonist inhibits lipopolysaccharide induced microglial activation and death. Neurochem Res. (2011) 36: 1587– 93. 10.1007/s11064-010-0336-7 21127968 PMC3951894 · DOI
  54. [59]Siani F Greco R Levandis G Ghezzi C Daviddi F Demartini C. Influence of estrogen modulation on glia activation in a murine model of Parkinson's disease. Front Neurosci. (2017) 11: 306. 10.3389/fnins.2017.00306 28620274 PMC5449471 · DOI
  55. [60]Dang J Mitkari B Kipp M Beyer C. Gonadal steroids prevent cell damage and stimulate behavioral recovery after transient middle cerebral artery occlusion in male and female rats. Brain Behav Immun. (2011) 25: 715– 26. 10.1016/j.bbi.2011.01.013 21277368 · DOI
  56. [61]Habib P Slowik A Zendedel A Johann S Dang J Beyer C. Regulation of hypoxia-induced inflammatory responses and M1-M2 phenotype switch of primary rat microglia by sex steroids. J Mol Neurosci. (2014) 52: 277– 85. 10.1007/s12031-013-0137-y 24163150 · DOI
  57. [62]Pepe G De Maglie M Minoli L Villa A Maggi A Vegeto E. Selective proliferative response of microglia to alternative polarizationsignals. J Neuroinflammation. (2017) 14: 236. 10.1186/s12974-017-1011-6 29202771 PMC5715534 · DOI

Cited by

Sorted by citations

Authors
Loiola, R. A., Wickstead, E. S., Solito, E., & McArthur, S.
Affiliations
Queen Mary University of London (GB)
Corresponding author
McArthur, Simon
ORCID
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2019-06-26
Volume
10
Pages
420-420
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2019.00420
PMC
PMC6607409
OpenAlex
W2954674333
Cited by
57
References
5
Citations by year
2026: 9 · 2025: 11 · 2024: 10 · 2023: 8 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 2
FWCI
2.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
Funders
  • Fondazione Italiana Sclerosi Multipla (2014/R, 2014/R21)
  • University of Westminster
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
estrogen, estradiol, annexin A1, microglia, estrogen receptor beta, G protein-coupled estrogen receptor, neuroinflammation, phagocytosis of apoptotic cells, brain injury, BV-2 cells

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