Abstract
According to our previous reports, impaired oocyte pickup was observed in the oviductal infundibulum of an autoimmune disease (AD) mouse model, suggesting a relationship between female infertility and AD. This study examines the relationship between AD and infundibulum morphofunction by focusing on the epithelial cilia. Healthy MRL/MpJ and AD-prone MRL/MpJ-Faslpr/lpr mice were examined at 3 and 6 months of age, representing early and late disease stages, respectively. Oocyte pickup indices decreased with AD progression indicated by splenomegaly, autoantibody production and increased T cell counts of infundibulum mucosa in MRL/MpJ-Faslpr/lpr mice. Ciliary beating frequency (CBF) and height in the infundibulum were faster and higher in MRL/MpJ-Faslpr/lpr mice than in MRL/MpJ mice at the early AD stages, although the absolute CBF values were lower at the late AD stage. At the late stage, ciliary height did not differ between mouse lines but the morphological index of cilia beating direction indicated randomized patterns in MRL/MpJ-Faslpr/lpr mice. The tracheal mucosa was also examined as a representative example of cilia morphology; its CBF decreased at the late AD stage in MRL/MpJ-Faslpr/lpr; however, there were no AD-related morphological changes. Our results demonstrate altered cilia motility in systemic and reproductive organs, with such morphological changes of the infundibulum likely impairing function, including oocyte pickup.
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Abbreviations
- CBF:
-
Ciliary beat frequency
- COC:
-
Cumulus oocyte complex
- D-MEM:
-
Dulbecco’s modified Eagle’s medium (high glucose) with L-glutamine and phenol red
- dsDNA:
-
Double-stranded DNA
- Fas:
-
Fas cell surface death receptor
- hCG:
-
Human chorionic gonadotropin
- lpr:
-
Lymphoproliferation
- MRL/+:
-
MRL/MpJ
- MRL/lpr:
-
MRL/MpJ-Faslpr/lpr
- OO:
-
Ovulated oocyte
- PB:
-
Phosphate buffer
- PBS:
-
Phosphate-buffered saline
- PCD:
-
Primary ciliary dyskinesia
- PFA:
-
Paraformaldehyde
- PMSG:
-
Pregnant mare serum gonadotropin
- PUR:
-
Oocyte pickup rate
- ROI:
-
Region of interest
- S/B:
-
Ratio of spleen weight to body weight
- TEM:
-
Transmission electron microscope
References
Andrews BS, Eisenberg RA, Theofilopoulos AN et al (1978) Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 148:1198–1215
Ardighieri L, Lonardi S, Moratto D et al (2014) Characterization of the immune cell repertoire in the normal fallopian tube. Int J Gynecol Pathol 33:581–591. https://doi.org/10.1097/PGP.0000000000000095
Armengot M, Milara J, Mata M et al (2010) Cilia motility and structure in primary and secondary ciliary dyskinesia. Artic Am J Rhinol Allergy 24:175–180. https://doi.org/10.2500/ajra.2010.24.3448
Avasthi P, Marshall WF (2012) Stages of ciliogenesis and regulation of ciliary length. Differentiation 83:S30–S42. https://doi.org/10.1016/J.DIFF.2011.11.015
Balomenos D, Rumold R, Theofilopoulos AN (1998) Interferon-ɤ is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J Clin Invest 101:364–371
Carp HJA, Selmi C (2012) The autoimmune bases of infertility and pregnancy loss. J Autoimmun 38:J266–J274. https://doi.org/10.1016/J.JAUT.2011.11.016
Chen JJ, Lemieux BT, Wong BJF (2016) A low-cost method of ciliary beat frequency measurement using iPhone and MATLAB. Otolaryngol Head Neck Surg 155:252–256. https://doi.org/10.1177/0194599816640219
Corbeel L, Cornillie F, Lauweryns J et al (1981) Ultrastructural abnormalities of bronchial cilia in children with recurrent airway infections and bronchiectasis. Arch Dis Child 56:929–933. https://doi.org/10.1136/ADC.56.12.929
Crow J, Amso NN, Lewin J, Shaw RW (1994) Morphology and ultrastructure of fallopian tube epithelium at different stages of the menstrual cycle and menopause. Hum Reprod 9:2224–2233. https://doi.org/10.1093/oxfordjournals.humrep.a138428
Dummer A, Rol N, Szulcek R et al (2018) Endothelial dysfunction in pulmonary arterial hypertension: loss of cilia length regulation upon cytokine stimulation. Pulm Circ 8:1–9. https://doi.org/10.1177/2045894018764629
Elewa YHA, Ichii O, Kon Y (2017) Sex-related differences in autoimmune-induced lung lesions in MRL/MpJ- faslpr mice are mediated by the development of mediastinal fat-associated lymphoid clusters. Autoimmunity 50:306–316. https://doi.org/10.1080/08916934.2017.1344973
Fang X, Zaman MH, Guo X et al (2018) Role of hepatic deposited immunoglobulin G in the pathogenesis of liver damage in systemic lupus erythematosus. Front Immunol 9:1457. https://doi.org/10.3389/fimmu.2018.01457
Gordts S, Campo R, Rombauts L, Brosens I (1998) Endoscopic visualization of the process of fimbrial ovum retrieval in the human. Hum Reprod 13:1425–1428. https://doi.org/10.1093/humrep/13.6.1425
Grosse-Onnebrink J, Werner C, Loges NT et al (2016) Effect of TH2 cytokines and interferon gamma on beat frequency of human respiratory cilia. Pediatr Res 79:731–735. https://doi.org/10.1038/pr.2016.8
Guirao B, Meunier A, Mortaud S et al (2010) Coupling between hydrodynamic forces and planar cell polarity orients mammalian motile cilia. Nat Cell Biol 12:341–350. https://doi.org/10.1038/ncb2040
Haller-Kikkatalo K, Salumets A, Uibo R (2012) Review on autoimmune reactions in female infertility: antibodies to follicle stimulating hormone. Clin Dev Immunol 2012:762541. https://doi.org/10.1155/2012/762541
Hosotani M, Ichii O, Nakamura T et al (2018) Autoimmune abnormality affects ovulation and oocyte-pick-up in MRL/MpJ-Fas lpr/lpr mice. Lupus 27:82–94. https://doi.org/10.1177/0961203317711772
Huang S, Driessen N, Knoll M, Talbot P (1997) In vitro analysis of oocyte cumulus complex pickup rate in the hamster Mesocricetus auratus. Mol Reprod Dev 47:312–322
Ichii O, Otsuka S, Sasaki N et al (2010) Local overexpression of interleukin-1 family, member 6 relates to the development of tubulointerstitial lesions. Lab Investig 90:459–475. https://doi.org/10.1038/labinvest.2009.148
Iwasaki A, Foxman EF, Molony RD (2017) Early local immune defences in the respiratory tract. Nat Rev Immunol 17:7–20. https://doi.org/10.1038/nri.2016.117
Kanno H, Nose M, Itoh J et al (1992) Spontaneous development of pancreatitis in the MRL/Mp strain of mice in autoimmune mechanism. Clin Exp Immunol 89:68–73
Klettke U, Luck W, Wahn U, Niggemann B (1999) Platelet-activating factor inhibits ciliary beat frequency of human bronchial epithelial cells. Allergy Asthma Proc 20:115–118
Kubaisi B, Samra KA, Foster CS (2016) Granulomatosis with polyangiitis (Wegener’s disease): an updated review of ocular disease manifestations. Intract Rare Dis Res 5:61–69. https://doi.org/10.5582/IRDR.2016.01014
Leigh MW, Pittman JE, Carson JL et al (2009) Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med 11:473–487. https://doi.org/10.1097/GIM.0b013e3181a53562
Liao SB, Li HWR, Ho JC et al (2012) Possible role of adrenomedullin in the pathogenesis of tubal ectopic pregnancy. J Clin Endocrinol Metab 97:2105–2112. https://doi.org/10.1210/jc.2011-3290
Luborsky J (2002) Ovarian autoimmune disease and ovarian autoantibodies. J Womens Health Gend Based Med 11:585–599
Lurie M, Tur-Kaspa I, Weill S et al (1989) Ciliary ultrastructure of respiratory and fallopian tube epithelium in a sterile woman with Kartagener’s syndrome: a quantitative estimation. Chest 95:578–581. https://doi.org/10.1378/CHEST.95.3.578
Magdy N, El-Bahrawy M (2014) Fallopian tube: its role in infertility and gynecological oncology. World J Obstet Gynecol 3:35–41. https://doi.org/10.5317/wjog.v3.i2.35
Mccomb P, Langley L, Sd M, Verdugo P (1986) The oviductal cilia and Kartagener’s syndrome. Fertil Steril 46:412–416. https://doi.org/10.1016/S0015-0282(16)49578-6
Nagata Y, Ichikawa T, Oakda H et al (2004) Views of infertile patients on application of assisted reproductive technologies for extra-marital state. J Fertil Implant 21:6–14
Niwa S, Nakajima K, Miki H et al (2012) KIF19A is a microtubule-depolymerizing kinesin for ciliary length control. Dev Cell 23:1167–1175. https://doi.org/10.1016/J.DEVCEL.2012.10.016
Norwood JT, Hein CE, Halbertt SA, Anderson RGW (1978) Polycationic macromolecules inhibit cilia-mediated ovum transport in the rabbit oviduct. Cell Biol 75:4413–4416
O WS, HWR L, Liao S-B et al (2013) Decreases in adrenomedullin expression and ciliary beat frequency in the nasal epithelium in tubal pregnancy. Fertil Steril 100:459–463.e1. https://doi.org/10.1016/J.FERTNSTERT.2013.04.007
Otani Y, Ichii O, Otsuka-Kanazawa S et al (2015) MRL/MpJ- Faslpr mice show abnormalities in ovarian function and morphology with the progression of autoimmune disease. Autoimmunity 48:402–411. https://doi.org/10.3109/08916934.2015.1031889
Papathanasiou A, Djahanbakhch O, Saridogan E, Lyons RA (2008) The effect of interleukin-6 on ciliary beat frequency in the human fallopian tube. Fertil Steril 90:391–394. https://doi.org/10.1016/j.fertnstert.2007.07.1379
Peters WM (1986) Nature of “basal” and “reserve” cells in oviductal and cervical epithelium in man. J Clin Pathol 39:306–312. https://doi.org/10.1136/jcp.39.3.306
Rautiainen M, Collan Y, Nuutinen J (1986) A method for measuring the orientation (“beat direction”) of respiratory cilia. Arch Otorhinolaryngol 243:265–268
Roupa Z, Polikandrioti M, Sotiropoulou P et al (2009) Causes of infertility in women at reproductive age. Health Sci J 3:80–87
Santiago-Raber M-L, Laporte C, Reininger L, Izui S (2004) Genetic basis of murine lupus. Autoimmun Rev 3:33–39. https://doi.org/10.1016/S1568-9972(03)00062-4
Sawamukai Y, Minami Y, Nakano T, De Silva LNA (2014) Tubal patency and fertility in repeat breeder cows. J Japan Vet Med Assoc 50:224–227. https://doi.org/10.12935/jvma1951.50.224
Sen A, Kushnir VA, Barad DH, Gleicher N (2014) Endocrine autoimmune diseases and female infertility. Nat Rev Endocrinol 10:37–50. https://doi.org/10.1038/nrendo.2013.212
Shi D, Komatsu K, Uemura T, Fujimori T (2011) Analysis of ciliary beat frequency and ovum transport ability in the mouse oviduct. Genes Cells 16:282–290. https://doi.org/10.1111/j.1365-2443.2011.01484.x
Shorter SL, Albaghdadi AJH, Kan FWK (2016) Alterations in oviductal cilia morphology and reduced expression of axonemal dynein in diabetic NOD mice. Tissue Cell 48:588–595. https://doi.org/10.1016/J.TICE.2016.10.003
Takeo T, Hoshii T, Kondo Y et al (2008) Methyl-beta-cyclodextrin improves fertilizing ability of C57BL/6 mouse sperm after freezing and thawing by facilitating cholesterol efflux from the cells. Biol Reprod 78:546–551. https://doi.org/10.1095/biolreprod.107.065359
Tang B, Matsuda T, Akira S et al (1991) Age-associated increase in interleukin 6 in MRL/lpr mice. Int Immunol 3:273–278. https://doi.org/10.1093/intimm/3.3.273
Thomas B, Rutman A, Hirst RA et al (2010) Ciliary dysfunction and ultrastructural abnormalities are features of severe asthma. J Allergy Clin Immunol 126:722–729.e2. https://doi.org/10.1016/j.jaci.2010.05.046
Ullrich S, Gustke H, Lamprecht P et al (2009) Severe impaired respiratory ciliary function in Wegener granulomatosis. Ann Rheum Dis 69:1067–1071. https://doi.org/10.1136/ard.2008.096974
Vanaken GJ, Bassinet L, Boon M et al (2017) Infertility in an adult cohort with primary ciliary dyskinesia: phenotype-gene association. Eur Respir J 50:1700314. https://doi.org/10.1183/13993003.00314-2017
Yang J-Q, Saxena V, Xu H et al (2003) Repeated α-galactosylceramide administration results in expansion of NK T cells and alleviates inflammatory dermatitis in MRL-lpr/lpr mice. J Immunol 171:4439–4446. https://doi.org/10.4049/jimmunol.171.8.4439
Yang J, Li Q, Yang X, Li M (2015) Interleukin-9 is associated with elevated anti-double-stranded DNA antibodies in lupus-prone mice. Mol Med 21:364–370. https://doi.org/10.2119/molmed.2014.00237
Acknowledgments
We are deeply grateful to Dr. Jason Chen for willingly supporting our CBF measurements by providing us his developed program.
Funding
This work was supported in part by JSPS KAKENHI Grant Number JP18J22313 (M. Hosotani).
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M. Hosotani designed, performed experiments and analyzed data. M.A. Masum and Y. Otani analyzed data. O. Ichii, T. Nakamura, Y.H.A. Elewa and Y. Kon designed and reviewed the experiments. M. Hosotani, O. Ichii and Y. Kon wrote the manuscript. All authors approved the final manuscript.
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Animal experimentation was approved by the Institutional Animal Care and Use Committee of the Graduate School of Veterinary Medicine, Hokkaido University (Approval No. 15-0079). Experimental animals were handled in accordance with the Guide for the Care and Use of Laboratory Animals, Graduate School of Veterinary Medicine, Hokkaido University (approved by the Association for Assessment and Accreditation of Laboratory Animal Care International).
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Online Resource 1.
The ciliary beating in the oviductal infundibulum of MRL/MpJ mice at 3 months. (MP4 243 kb)
Online Resource 2.
The ciliary beating in the oviductal infundibulum of MRL/MpJ mice at 6 months. (MP4 366 kb)
Online Resource 3.
The ciliary beating in the oviductal infundibulum of MRL/MpJ-Faslpr/lpr mice at 3 months. (MP4 257 kb)
Online Resource 4.
The ciliary beating in the oviductal infundibulum of MRL/MpJ-Faslpr/lpr mice at 6 months. (MP4 168 kb)
Online Resource 5.
The ciliary beating in the trachea of MRL/MpJ mice at 3 months. (MP4 289 kb)
Online Resource 6.
The ciliary beating in the trachea of MRL/MpJ mice at 6 months. (MP4 354 kb)
Online Resource 7.
The ciliary beating in the trachea of MRL/MpJ-Faslpr/lpr mice at 3 months. (MP4 370 kb)
Online Resource 8.
The ciliary beating in the trachea of MRL/MpJ-Faslpr/lpr mice at 6 months. (MP4 583 kb)
Supplementary Figure S1.
Scheme of the preparation for the ciliary beat frequency measurement. (a) Oviductal infundibulum preparation schematic. The infundibulum is placed into the drop of D-MEM (high glucose) with L-Glutamine and phenol red (D-MEM) and covered with a cover slip so that the ciliated epithelium faces the cover slip. (b) Trachea preparation schematic. The pieces of trachea are placed into D-MEM on a slide and sealed with a cover slip. (PNG 27 kb)
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Hosotani, M., Ichii, O., Nakamura, T. et al. Altered ciliary morphofunction in the oviductal infundibulum of systemic autoimmune disease-prone MRL/MpJ-Faslpr/lpr mice. Cell Tissue Res 380, 627–641 (2020). https://doi.org/10.1007/s00441-020-03175-z
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DOI: https://doi.org/10.1007/s00441-020-03175-z