Animal Reproduction (AR)
https://animal-reproduction.org/article/doi/10.1590/1984-3143-AR2021-0009
Animal Reproduction (AR)
ORIGINAL ARTICLE

Early pregnancy affects expression of Toll-like receptor signaling members in ovine spleen

Leying Zhang; Gengxin Yang; Qiongao Zhang; Pengfei Feng; Meihong Gao; Ling Yang

Downloads: 0
Views: 610

Abstract

Toll-like receptors (TLRs) are involved to the maternal immune tolerance. The spleen is essential for adaptive immune reactions. However, it is unclear that early pregnancy regulates TLR-mediated signalings in the maternal spleen. The purpose of this study was to investigate the effects of early pregnancy on expression of TLR signaling members in the ovine spleen. Ovine spleens were collected at day 16 of the estrous cycle, and at days 13, 16 and 25 of pregnancy (n = 6 for each group). Real-time quantitative PCR, western blot and immunohistochemistry analysis were used to detect TLR signaling members, including TLR2, TLR3, TLR4, TLR5, TLR7, TLR9, myeloid differentiation primary-response protein 88 (MyD88), tumor necrosis factor receptor associated factor 6 (TRAF6) and interleukin-1-receptor-associated kinase 1 (IRAK1). The results showed that expression levels of TLR2, TLR4 and IRAK1 were downregulated, but expression levels of TLR3, TLR5, TLR7, TLR9, TRAF6 and MyD88 were increased during early pregnancy. In addition, MyD88 protein was located in the capsule, trabeculae and splenic cords of the maternal spleen. This paper reports for the first time that early pregnancy has effects on TLR signaling pathways in the ovine spleen, which is beneficial for understanding the maternal immune tolerance during early pregnancy.

Keywords

toll-like receptors, pregnancy, spleen, sheep

References

Abrahams VM, Mor G. Toll-like receptors and their role in the trophoblast. Placenta. 2005;26(7):540-7. http://dx.doi.org/10.1016/j.placenta.2004.08.010. PMid:15993703.

Akiyama T, Shimo Y, Yanai H, Qin J, Ohshima D, Maruyama Y, Asaumi Y, Kitazawa J, Takayanagi H, Penninger JM, Matsumoto M, Nitta T, Takahama Y, Inoue J. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity. 2008;29(3):423-37. http://dx.doi.org/10.1016/j.immuni.2008.06.015. PMid:18799149.

Amirchaghmaghi E, Taghavi SA, Shapouri F, Saeidi S, Rezaei A, Aflatoonian R. The role of toll like receptors in pregnancy. Int J Fertil Steril. 2013;7(3):147-54. PMid:24520479.

Atli MO, Kose M, Hitit M, Kaya MS, Bozkaya F. Expression patterns of Toll-like receptors in the ovine corpus luteum during the early pregnancy and prostaglandin F2α-induced luteolysis. Theriogenology. 2018;111:25-33. http://dx.doi.org/10.1016/j.theriogenology.2018.01.010. PMid:29407424.

Bai J, Zhang L, Zhao Z, Li N, Wang B, Yang L. Expression of melatonin receptors and CD4 in the ovine thymus, lymph node, spleen and liver during early pregnancy. Immunology. 2020;160(1):52-63. http://dx.doi.org/10.1111/imm.13180. PMid:32052861.

Barboza R, Lima FA, Reis AS, Murillo OJ, Peixoto EPM, Bandeira CL, Fotoran WL, Sardinha LR, Wunderlich G, Bevilacqua E, Lima MRD, Alvarez JM, Costa FTM, Gonçalves LA, Epiphanio S, Marinho CRF. TLR4-mediated placental pathology and pregnancy outcome in experimental malaria. Sci Rep. 2017;7(1):8623. http://dx.doi.org/10.1038/s41598-017-08299-x. PMid:28819109.

Borrello S, Nicolò C, Delogu G, Pandolfi F, Ria F. TLR2: a crossroads between infections and autoimmunity? Int J Immunopathol Pharmacol. 2011;24(3):549-56. http://dx.doi.org/10.1177/039463201102400301. PMid:21978687.

Bott RC, Ashley RL, Henkes LE, Antoniazzi AQ, Bruemmer JE, Niswender GD, Bazer FW, Spencer TE, Smirnova NP, Anthony RV, Hansen TR. Uterine vein infusion of interferon tau (IFNT) extends luteal life span in ewes. Biol Reprod. 2010;82(4):725-35. http://dx.doi.org/10.1095/biolreprod.109.079467. PMid:20042537.

Brendolan A, Rosado MM, Carsetti R, Selleri L, Dear TN. Development and function of the mammalian spleen. BioEssays. 2007;29(2):166-77. http://dx.doi.org/10.1002/bies.20528. PMid:17226804.

Bustamante JJ, Dai G, Soares MJ. Pregnancy and lactation modulate maternal splenic growth and development of the erythroid lineage in the rat and mouse. Reprod Fertil Dev. 2008;20(2):303-10. http://dx.doi.org/10.1071/RD07106. PMid:18255020.

Butcher SK, O’Carroll CE, Wells CA, Carmody RJ. Toll-like receptors drive specific patterns of tolerance and training on restimulation of macrophages. Front Immunol. 2018;9:933. http://dx.doi.org/10.3389/fimmu.2018.00933. PMid:29867935.

Cao N, Cao L, Gao M, Wang H, Zhang L, Yang L. Changes in mRNA and protein levels of gonadotropin releasing hormone and receptor in ovine thymus, lymph node, spleen and liver during early pregnancy. Domest Anim Endocrinol. 2021;76:106607. http://dx.doi.org/10.1016/j.domaniend.2021.106607. PMid:33582417.

Cervantes JL. MyD88 in Mycobacterium tuberculosis infection. Med Microbiol Immunol. 2017;206(3):187-93. http://dx.doi.org/10.1007/s00430-017-0495-0. PMid:28220253.

Cesta MF. Normal structure, function, and histology of the spleen. Toxicol Pathol. 2006;34(5):455-65. http://dx.doi.org/10.1080/01926230600867743. PMid:17067939.

Godkin JD, Bazer FW, Moffatt J, Sessions F, Roberts RM. Purification and properties of a major, low molecular weight protein released by the trophoblast of sheep blastocysts at day 13-21. J Reprod Fertil. 1982;65(1):141-50. http://dx.doi.org/10.1530/jrf.0.0650141. PMid:7077590.

Hansen TR, Sinedino LDP, Spencer TE. Paracrine and endocrine actions of interferon tau (IFNT). Reproduction. 2017;154(5):F45-59. http://dx.doi.org/10.1530/REP-17-0315. PMid:28982937.

Hegde UC, Ranpura S, D’Souza S, Raghavan VP. Immunoregulatory pathways in pregnancy. Indian J Biochem Biophys. 2001;38(4):207-19. PMid:11811615.

Imakawa K, Bai R, Nakamura K, Kusama K. Thirty years of interferon-tau research; Past, present and future perspective. Anim Sci J. 2017;88(7):927-36. http://dx.doi.org/10.1111/asj.12807. PMid:28504476.

Kandil D, Leiman G, Allegretta M, Trotman W, Pantanowitz L, Goulart R, Evans M. Glypican-3 immunocytochemistry in liver fine-needle aspirates: a novel stain to assist in the differentiation of benign and malignant liver lesions. Cancer. 2007;111(5):316-22. http://dx.doi.org/10.1002/cncr.22954. PMid:17763368.

Karen A, Beckers JF, Sulon J, de Sousa NM, Szabados K, Reczigel J, Szenci O. Early pregnancy diagnosis in sheep by progesterone and pregnancy-associated glycoprotein tests. Theriogenology. 2003;59(9):1941-8. http://dx.doi.org/10.1016/S0093-691X(02)01289-X. PMid:12600731.

Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11(5):373-84. http://dx.doi.org/10.1038/ni.1863. PMid:20404851.

Kaya MS, Kose M, Guzeloglu A, Kıyma Z, Atli MO. Early pregnancy-related changes in toll-like receptors expression in ovine trophoblasts and peripheral blood leukocytes. Theriogenology. 2017;93:40-5. http://dx.doi.org/10.1016/j.theriogenology.2017.01.031. PMid:28257865.

Koga K, Mor G. Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy disorders. Am J Reprod Immunol. 2010;63(6):587-600. http://dx.doi.org/10.1111/j.1600-0897.2010.00848.x. PMid:20367625.

Kuang P, Guo H, Deng H, Cui H, Fang J, Zuo Z, Deng J, Li Y, Wang X, Zhao L. Sodium fluoride impairs splenic innate immunity via inactivation of TLR2/MyD88 signaling pathway in mice. Chemosphere. 2019;237:124437. http://dx.doi.org/10.1016/j.chemosphere.2019.124437. PMid:31356994.

Lalive PH, Benkhoucha M, Tran NL, Kreutzfeldt M, Merkler D, Santiago-Raber ML. TLR7 signaling exacerbates CNS autoimmunity through downregulation of Foxp3+ Treg cells. Eur J Immunol. 2014;44(1):46-57. http://dx.doi.org/10.1002/eji.201242985. PMid:24018482.

Letran SE, Lee SJ, Atif SM, Uematsu S, Akira S, McSorley SJ. TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity. Eur J Immunol. 2011;41(1):29-38. http://dx.doi.org/10.1002/eji.201040717. PMid:21182074.

Li N, Wang L, Cao N, Zhang L, Han X, Yang L. Early pregnancy affects the expression of toll-like receptor pathway in ovine thymus. Reprod Biol. 2020;20(4):547-54. http://dx.doi.org/10.1016/j.repbio.2020.10.003. PMid:33158780.

Li N, Zhao Z, Bai J, Liu B, Mi H, Zhang L, Li G, Yang L. Characterization of the Th cytokines profile in ovine spleen during early pregnancy. J Appl Anim Res. 2019;47(1):386-93. http://dx.doi.org/10.1080/09712119.2019.1634077.

Lorek D, Kedzierska AE, Slawek A, Chelmonska-Soyta A. Expression of Toll-like receptors and costimulatory molecules in splenic B cells in a normal and abortion-prone murine pregnancy model. Am J Reprod Immunol. 2019;82(2):e13148. http://dx.doi.org/10.1111/aji.13148. PMid:31134706.

Lyttle B, Chai J, Gonzalez JM, Xu H, Sammel M, Elovitz MA. The negative regulators of the host immune response: an unexplored pathway in preterm birth. Am J Obstet Gynecol. 2009;201(3):284.e1. http://dx.doi.org/10.1016/j.ajog.2009.05.053. PMid:19733281.

McNatty KP, Revefeim KJ, Young A. Peripheral plasma progesterone concentrations in sheep during the oestrous cycle. J Endocrinol. 1973;58(2):219-25. http://dx.doi.org/10.1677/joe.0.0580219. PMid:4737738.

Nagelkerke SQ, Bruggeman CW, den Haan JMM, Mul EPJ, van den Berg TK, van Bruggen R, Kuijpers TW. Red pulp macrophages in the human spleen are a distinct cell population with a unique expression of Fc-γ receptors. Blood Adv. 2018;2(8):941-53. http://dx.doi.org/10.1182/bloodadvances.2017015008. PMid:29692344.

Oliveira JF, Henkes LE, Ashley RL, Purcell SH, Smirnova NP, Veeramachaneni DN, Anthony RV, Hansen TR. Expression of interferon (IFN)-stimulated genes in extrauterine tissues during early pregnancy in sheep is the consequence of endocrine IFN-tau release from the uterine vein. Endocrinology. 2008;149(3):1252-9. http://dx.doi.org/10.1210/en.2007-0863. PMid:18063687.

Prearo Moço N, Camargo Batista RA, Fernandes Martin L, Oliveira LG, Parada CMGL, Alarcão Dias-Melicio L, Golim MA, Guimarães da Silva M. Toll-like receptor-2 and -4 expression by maternal neutrophils in preterm labor. Gynecol Obstet Invest. 2018;83(1):1-8. http://dx.doi.org/10.1159/000468930. PMid:28359059.

Ruiz-González I, Minten M, Wang X, Dunlap KA, Bazer FW. Involvement of TLR7 and TLR8 in conceptus development and establishment of pregnancy in sheep. Reproduction. 2015;149(4):305-16. http://dx.doi.org/10.1530/REP-14-0537. PMid:25602033.

Salio M, Cerundolo V. Viral immunity: cross-priming with the help of TLR3. Curr Biol. 2005;15(9):R336-9. http://dx.doi.org/10.1016/j.cub.2005.04.025. PMid:15886091.

Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101-8. http://dx.doi.org/10.1038/nprot.2008.73. PMid:18546601.

Steiniger BS. Human spleen microanatomy: why mice do not suffice. Immunology. 2015;145(3):334-46. http://dx.doi.org/10.1111/imm.12469. PMid:25827019.

Vollmer J. TLR9 in health and disease. Int Rev Immunol. 2006;25(3-4):155-81. http://dx.doi.org/10.1080/08830180600743107. PMid:16818370.

Walsh MC, Lee J, Choi Y. Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev. 2015;266(1):72-92. http://dx.doi.org/10.1111/imr.12302. PMid:26085208.

Wang B, Koga K, Osuga Y, Cardenas I, Izumi G, Takamura M, Hirata T, Yoshino O, Hirota Y, Harada M, Mor G, Taketani Y. Toll-like receptor-3 ligation-induced indoleamine 2, 3-dioxygenase expression in human trophoblasts. Endocrinology. 2011;152(12):4984-92. http://dx.doi.org/10.1210/en.2011-0278. PMid:21952237.

Wang Y, Han X, Zhang L, Cao N, Cao L, Yang L. Early pregnancy induces expression of STAT1, OAS1 and CXCL10 in ovine spleen. Animals. 2019;9(11):882. http://dx.doi.org/10.3390/ani9110882. PMid:31671580.

Xie F, Hu Y, Turvey SE, Magee LA, Brunham RM, Choi KC, Krajden M, Leung PC, Money DM, Patrick DM, Thomas E, von Dadelszen P. Toll-like receptors 2 and 4 and the cryopyrin inflammasome in normal pregnancy and pre-eclampsia. BJOG. 2010;117(1):99-108. http://dx.doi.org/10.1111/j.1471-0528.2009.02428.x. PMid:20002372.

Yang L, Guo R, Yao X, Yan J, Bai Y, Zhang L. Expression of progesterone receptor and progesterone-induced blocking factor in the spleen during early pregnancy in ewes. Livest Sci. 2018a;209:14-9. http://dx.doi.org/10.1016/j.livsci.2018.01.004.

Yang L, Liu Y, Lv W, Wang P, Wang B, Xue J, Zhang L. Expression of interferon-stimulated gene 15-kDa protein, cyclooxygenase (COX) 1, COX-2, aldo-keto reductase family 1, member B1, and prostaglandin E synthase in the spleen during early pregnancy in sheep. Anim Sci J. 2018b;89(11):1540-8. http://dx.doi.org/10.1111/asj.13101. PMid:30191656.

Yang L, Li N, Zhang L, Bai J, Zhao Z, Wang Y. Effects of early pregnancy on expression of interferon-stimulated gene 15, STAT1, OAS1, MX1, and IP-10 in ovine liver. Anim Sci J. 2020;91(1):e13378. http://dx.doi.org/10.1111/asj.13378. PMid:32329195.

Yang L, Liu B, Yan X, Zhang L, Gao F, Liu Z. Expression of ISG15 in bone marrow during early pregnancy in ewes. Kafkas Univ Vet Fak Derg. 2017;23:767-72.

Yang L, Wang Q, Liu Y, Zhang L, Lv W, Liu B. Expression profiles of interferon-stimulated gene 15 and prostaglandin synthases in the ovine lymph nodes during early pregnancy. Mol Reprod Dev. 2019;86(1):100-8. http://dx.doi.org/10.1002/mrd.23085. PMid:30411425.

Yoo I, Han J, Lee S, Jung W, Kim JH, Kim YW, Kim HJ, Hong M, Ka H. Analysis of stage-specific expression of the toll-like receptor family in the porcine endometrium throughout the estrous cycle and pregnancy. Theriogenology. 2019;125:173-83. http://dx.doi.org/10.1016/j.theriogenology.2018.11.003. PMid:30448720.

Zhang L, Xue J, Wang Q, Lv W, Mi H, Liu Y, Yang L. Changes in expression of ISG15, progesterone receptor and progesterone-induced blocking factor in ovine thymus during early pregnancy. Theriogenology. 2018;121:153-9. http://dx.doi.org/10.1016/j.theriogenology.2018.08.018. PMid:30149261.

Zhang L, Cao L, Yang F, Han X, Wang Y, Cao N, Yang L. Relative abundance of interferon-stimulated genes STAT1, OAS1, CXCL10 and MX1 in ovine lymph nodes during early pregnancy. Anim Reprod Sci. 2020a;214:106285. http://dx.doi.org/10.1016/j.anireprosci.2020.106285. PMid:32087912.

Zhang L, Zhao Z, Wang Y, Li N, Cao N, Yang L. Changes in expression of interferon-stimulated genes and ubiquitin activating enzyme E1-like in ovine thymus during early pregnancy. Anim Reprod. 2020b;17(2):e20190134. http://dx.doi.org/10.1590/1984-3143-ar2019-0134. PMid:32714456.

Zhao L, Li J, Huang S. Patients with unexplained recurrent spontaneous abortion show decreased levels of microrna-146a-5p in the deciduae. Ann Clin Lab Sci. 2018;48(2):177-82. PMid:29678844.
 


Submitted date:
02/02/2021

Accepted date:
06/30/2021

610c021ba9539506340fa373 animreprod Articles
Links & Downloads

Anim Reprod

Share this page
Page Sections