title: Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice?
abstract: Researchers have proposed that estrogen deficiency will lead to a Sjögren's syndrome (SjS)-like lacrimal gland inflammation, aqueous tear deficiency and dry eye. The purpose of this study was to determine whether this proposal is correct. Lacrimal glands were obtained from adult, age-matched wild type (WT) and aromatase knockout (ArKO) mice, in which estrogen synthesis is completely eliminated. Tissues were also obtained from autoimmune MRL/Mp-lpr/lpr (MRL/lpr) mice as inflammation controls. Tear volumes in WT and ArKO mice were measured and glands were processed for molecular biological and histological evaluation. Our results demonstrate that estrogen absence does not lead to a SjS-like inflammation in lacrimal tissue or to an aqueous-deficient dry eye. There was no upregulation of genes associated with inflammatory pathways in lacrimal glands of male or female ArKO mice. Such inflammatory activity was prominent in autoimmune MRL/lpr tissues. We also found no evidence of inflammation in lacrimal gland tissue sections of estrogen-deficient mice, and tear volumes of ArKO males were actually increased as compared to those WT controls. Interestingly, our study did show that estrogen absence influences the expression of thousands of lacrimal gland genes, and that this impact is sex- and genotype-specific. Our findings demonstrate that estrogen absence is not a risk factor for the development of SjS-like lacrimal gland inflammation or for aqueous-deficient dry eye in mice.
authors.affiliation: Schepens Eye Research Institute, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
authors.forename: Raheleh
authors.initials: R
authors.lastname: Rahimi Darabad
authors.affiliation: Schepens Eye Research Institute, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
authors.forename: Tomo
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Schepens Eye Research Institute, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Richards
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Jakobiec
authors.affiliation: Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Massachusetts Eye and Ear Infirmary, Boston, MA, USA.
authors.forename: Fouad R
authors.initials: FR
authors.lastname: Zakka
authors.affiliation: Schepens Eye Research Institute, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Barabino
authors.affiliation: Schepens Eye Research Institute, Boston, MA, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Massachusetts Eye and Ear Infirmary, Boston, MA, USA. Electronic address: david.sullivan@schepens.harvard.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Sullivan
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D001141:Aromatase / Q000235:genetics; D003607:Dacryocystitis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015352:Dry Eye Syndromes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004967:Estrogens / Q000172:deficiency*; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000502:physiology; D005838:Genotype; D007765:Lacrimal Apparatus / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D012737:Sex Factors; D015854:Up-Regulation
chemical_list: D004967:Estrogens; D005136:Eye Proteins; D001141:Aromatase
keywords: estrogen; female; gene expression; inflammation; lacrimal gland; male; mice; sex difference; tear volume
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12628-33
references.pmid: 15314222
references.citation: Mol Cell Neurosci. 2004 Dec;27(4):466-76
references.pmid: 15555924
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6965-70
references.pmid: 9618522
references.citation: Invest Ophthalmol Vis Sci. 1994 Apr;35(5):2632-42
references.pmid: 8163351
references.citation: Biochem Biophys Res Commun. 2006 Mar 24;341(4):1286-93
references.pmid: 16469299
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3507-12
references.pmid: 23401516
references.citation: Psychopharmacology (Berl). 2009 Oct;206(2):267-79
references.pmid: 19597801
references.citation: Mol Vis. 2009 Aug 10;15:1553-72
references.pmid: 19693291
references.citation: Exp Eye Res. 2009 Mar;88(3):334-8
references.pmid: 18619437
references.citation: Invest Ophthalmol Vis Sci. 2005 Aug;46(8):2766-71
references.pmid: 16043849
references.citation: Endocr Rev. 1996 Aug;17(4):369-84
references.pmid: 8854050
references.citation: J Appl Physiol (1985). 2001 Nov;91(5):2384-8
references.pmid: 11641384
references.citation: Exp Eye Res. 1999 Oct;69(4):355-66
references.pmid: 10504269
references.citation: Trends Genet. 2005 May;21(5):298-305
references.pmid: 15851067
references.citation: Curr Opin Rheumatol. 2004 Sep;16(5):522-6
references.pmid: 15314488
references.citation: Clin Exp Immunol. 1990 Jun;80(3):467-73
references.pmid: 2372993
references.citation: JAMA. 2001 Nov 7;286(17):2114-9
references.pmid: 11694152
references.citation: Scand J Immunol. 2000 Oct;52(4):393-400
references.pmid: 11013011
references.citation: Gen Comp Endocrinol. 2008 Sep 15;158(3):268-76
references.pmid: 18703064
references.citation: Genome Biol. 2003;4(1):R7
references.pmid: 12540299
references.citation: Exp Eye Res. 2012 Mar;96(1):88-97
references.pmid: 22227485
references.citation: J Clin Endocrinol Metab. 2009 Jun;94(6):2044-51
references.pmid: 19318446
references.citation: Invest Ophthalmol Vis Sci. 2013 Feb 05;54(2):987-98
references.pmid: 23233261
references.citation: Exp Eye Res. 2003 Sep;77(3):347-54
references.pmid: 12907167
references.citation: Prog Brain Res. 2010;181:177-92
references.pmid: 20478438
references.citation: J Interferon Cytokine Res. 2011 Dec;31(12):857-65
references.pmid: 22149411
references.citation: J Clin Endocrinol Metab. 1999 Dec;84(12):4677-94
references.pmid: 10599737
references.citation: Exp Eye Res. 2008 Sep;87(3):184-90
references.pmid: 18653183
references.citation: Clin Exp Optom. 2014 Jul;97(4):324-36
references.pmid: 24689906
references.citation: Exp Eye Res. 2007 May;84(5):960-72
references.pmid: 17399702
references.citation: Nat Genet. 2000 May;25(1):25-9
references.pmid: 10802651
references.citation: J Steroid Biochem Mol Biol. 1991;40(4-6):619-37
references.pmid: 1958562
references.citation: JAMA. 2006 Mar 22;295(12):1428-33
references.pmid: 16551715
references.citation: Ann Rheum Dis. 2003 Apr;62(4):341-6
references.pmid: 12634234
references.citation: Am J Pathol. 2003 Oct;163(4):1481-90
references.pmid: 14507655
references.citation: Immunotherapy. 2010 May;2(3):339-46
references.pmid: 20635899
references.citation: Maturitas. 2003 Jan 30;44(1):63-8
references.pmid: 12568737
references.citation: Brain Res. 2006 Dec 18;1126(1):50-5
references.pmid: 16962077
references.citation: Am J Pathol. 1999 Jul;155(1):173-81
references.pmid: 10393849
references.citation: J Steroid Biochem Mol Biol. 2001 Dec;79(1-5):181-5
references.pmid: 11850223
references.citation: Endocrinology. 2003 Sep;144(9):3895-903
references.pmid: 12933663
references.citation: Ocul Surf. 2007 Apr;5(2):93-107
references.pmid: 17508117
references.citation: Menopause. 2003 Jan-Feb;10(1):53-7
references.pmid: 12544677
references.citation: Nat Immunol. 2001 Sep;2(9):777-80
references.pmid: 11526384
references.citation: Ophthalmologica. 2004 Jul-Aug;218(4):257-9
references.pmid: 15258414
references.citation: Endocrinology. 2001 Jun;142(6):2458-67
references.pmid: 11356695
references.citation: Eur J Ophthalmol. 2003 May;13(4):337-42
references.pmid: 12872789
references.citation: J Autoimmun. 2012 Aug;39(1-2):49-56
references.pmid: 22300712
references.citation: Gen Comp Endocrinol. 2007 Apr;151(2):172-9
references.pmid: 17316636
references.citation: Cytogenet Genome Res. 2002;99(1-4):36-43
references.pmid: 12900543
references.citation: Gend Med. 2007;4 Suppl B:S75-95
references.pmid: 18156105
references.citation: Exp Eye Res. 2006 Jan;82(1):13-23
references.pmid: 15979613
references.citation: Br J Ophthalmol. 2014 Mar;98(3):371-6
references.pmid: 24390165
references.citation: Menopause. 2003 Sep-Oct;10(5):482-7
references.pmid: 14501611
references.citation: Endocrinology. 2004 Apr;145(4):1842-8
references.pmid: 14684602
references.citation: J Exp Med. 2008 Nov 24;205(12):2915-27
references.pmid: 19015307
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12735-40
references.pmid: 11070087
references.citation: Endocr Rev. 2005 May;26(3):322-30
references.pmid: 15817672
references.citation: Invest Ophthalmol Vis Sci. 2014 Feb 04;55(2):745-51
references.pmid: 24334444
references.citation: Invest Ophthalmol Vis Sci. 2006 Jan;47(1):158-68
references.pmid: 16384958
references.citation: Clin Exp Immunol. 1997 Sep;109(3):555-61
references.pmid: 9328136
references.citation: Arthritis Rheum. 1978 Jun;21(5 Suppl):S58-63
references.pmid: 352366
references.citation: Ocul Surf. 2004 Apr;2(2):92-123
references.pmid: 17216082
references.citation: J Nutr. 2003 Nov;133(11):3610-3
references.pmid: 14608082
references.citation: Horm Res. 1998;49 Suppl 1:2-8
references.pmid: 9554463
references.citation: Cell Immunol. 1996 Oct 10;173(1):55-63
references.pmid: 8871601
references.citation: J Autoimmun. 1989 Aug;2(4):543-52
references.pmid: 2789656
references.citation: J Exp Med. 1978 Jun 1;147(6):1568-83
references.pmid: 308087