Toll-like receptors at the maternal-fetal interface in normal pregnancy and pregnancy complications

American Journal of Reproductive Immunology

Volumn 72, Issue 2, 2014, Pages 192-205

  Koga, Kaori ^a   Izumi, Gentaro ^a   Mor, Gil ^b   Fujii, Tomoyuki ^a   Osuga, Yutaka ^a  

^a UNIVERSITY OF TOKYO   (Japan)

^b YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Decidua; Fetus; Inflammation; Preeclampsia; Preterm labor; Trophoblast

Indexed keywords

TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 2; TOLL LIKE RECEPTOR 3; TOLL LIKE RECEPTOR 4; TOLL LIKE RECEPTOR 9;

AMNION; ANTIVIRAL ACTIVITY; CELL FUNCTION; DECIDUA; FETUS DEVELOPMENT; FIRST TRIMESTER PREGNANCY; GENE EXPRESSION; GENETIC POLYMORPHISM; HUMAN; HYPOTHESIS; INNATE IMMUNITY; MICROORGANISM; MOLECULAR RECOGNITION; MOTHER FETUS RELATIONSHIP; NONHUMAN; PREECLAMPSIA; PREGNANCY; PREGNANCY COMPLICATION; PREMATURE LABOR; PRIORITY JOURNAL; PROGENY; REVIEW; SIGNAL TRANSDUCTION; TROPHOBLAST; ANIMAL; BACTERIAL INFECTION; EMBRYO DEATH; FEMALE; FETOMATERNAL TRANSFUSION; GENE EXPRESSION REGULATION; GENETICS; IMMUNOLOGY; MICROBIOLOGY; PATHOLOGY; VIROLOGY; VIRUS INFECTION;

ANIMALS; BACTERIAL INFECTIONS; DECIDUA; EMBRYO LOSS; FEMALE; GENE EXPRESSION REGULATION; HUMANS; MATERNAL-FETAL EXCHANGE; OBSTETRIC LABOR, PREMATURE; PRE-ECLAMPSIA; PREGNANCY; PREGNANCY COMPLICATIONS, INFECTIOUS; SIGNAL TRANSDUCTION; TOLL-LIKE RECEPTORS; TROPHOBLASTS; VIRUS DISEASES;

EID: 84904366810     PISSN: 10467408     EISSN: 16000897     Source Type: Journal    
DOI: 10.1111/aji.12258     Document Type: Review

References (128)

1. Romero R, Espinoza J, Goncalves LF, Kusanovic JP, Friel L, Hassan S: The role of inflammation and infection in preterm birth. Semin Reprod Med 2007; 25:21-39.
2. Goldenberg RL, Hauth JC, Andrews WW: Intrauterine infection and preterm delivery. N Engl J Med 2000; 342:1500-1507.
3. Arechavaleta-Velasco F, Gomez L, Ma Y, Zhao J, McGrath CM, Sammel MD, Nelson DB, Parry S: Adverse reproductive outcomes in urban women with adeno-associated virus-2 infections in early pregnancy. Hum Reprod 2008; 23:29-36.
4. Medzhitov R, Janeway CA Jr: Decoding the patterns of self and nonself by the innate immune system. Science 2002; 296:298-300.
5. Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D: Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Hum Reprod 1991; 6:791-798.
6. Bulmer JN, Pace D, Ritson A: Immunoregulatory cells in human decidua: morphology, immunohistochemistry and function. Reprod Nutr Dev 1988; 28:1599-1613.
7. Kammerer U, Schoppet M, McLellan AD, Kapp M, Huppertz HI, Kampgen E, Dietl J: Human decidua contains potent immunostimulatory CD83(+) dendritic cells. Am J Pathol 2000; 157:159-169.
8. Kammerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, Dietl J, van Kooyk Y, Kampgen E: Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. Am J Pathol 2003; 162:887-896.
9. Medzhitov R, Janeway CA Jr: Innate immunity: the virtues of a nonclonal system of recognition. Cell 1997; 91:295-298.
10. Gordon S: Pattern recognition receptors: doubling up for the innate immune response. Cell 2002; 111:927-930.
11. Abrahams VM: The role of the Nod-like receptor family in trophoblast innate immune responses. J Reprod Immunol 2011; 88:112-117.
12. Takeda K, Akira S: Roles of Toll-like receptors in innate immune responses. Genes Cells 2001; 6:733-742.
13. Zhang G, Ghosh S: Negative regulation of toll-like receptor-mediated signaling by Tollip. J Biol Chem 2002; 277:7059-7065.
14. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Bussey C, Flavell RA, Ghosh S: A toll-like receptor that prevents infection by uropathogenic bacteria. Science 2004; 303:1522-1526.
15. Yarovinsky F, Zhang D, Andersen JF, Bannenberg GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, Flavell RA, Ghosh S, Sher A: TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science 2005; 308:1626-1629.
16. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B: Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282:2085-2088.
17. Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, Klimpel GR, Godowski P, Zychlinsky A: Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. Science 1999; 285:736-739.
18. Aliprantis AO, Yang RB, Weiss DS, Godowski P, Zychlinsky A: The apoptotic signaling pathway activated by Toll-like receptor-2. EMBO J 2000; 19:3325-3336.
19. Schwandner R, Dziarski R, Wesche H, Rothe M, Kirschning CJ: Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem 1999; 274:17406-17409.
20. Krutzik SR, Ochoa MT, Sieling PA, Uematsu S, Ng YW, Legaspi A, Liu PT, Cole ST, Godowski PJ, Maeda Y, Sarno EN, Norgard MV, Brennan PJ, Akira S, Rea TH, Modlin RL: Activation and regulation of Toll-like receptors 2 and 1 in human leprosy. Nat Med 2003; 9:525-532.
21. Triantafilou M, Gamper FG, Haston RM, Mouratis MA, Morath S, Hartung T, Triantafilou K: Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting. J Biol Chem 2006; 281:31002-31011.
22. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413:732-738.
23. Diebold SS, Kaisho T, Hemmi H, Akira S, Reis e Sousa C: Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 2004; 303:1529-1531.
24. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S: Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science 2004; 303:1526-1529.
25. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, Sanjo H, Matsumoto M, Hoshino K, Wagner H, Takeda K, Akira S: A Toll-like receptor recognizes bacterial DNA. Nature 2000; 408:740-745.
26. Hochrein H, Schlatter B, O'Keeffe M, Wagner C, Schmitz F, Schiemann M, Bauer S, Suter M, Wagner H: Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways. Proc Natl Acad Sci USA 2004; 101:11416-11421.
27. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A: Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 2003; 198:513-520.
28. Frantz S, Kelly RA, Bourcier T: Role of TLR-2 in the activation of nuclear factor kappaB by oxidative stress in cardiac myocytes. J Biol Chem 2001; 276:5197-5203.
29. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E: Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279:7370-7377.
30. Guillot L, Balloy V, McCormack FX, Golenbock DT, Chignard M, Si-Tahar M: Cutting edge: the immunostimulatory activity of the lung surfactant protein-A involves Toll-like receptor 4. J Immunol 2002; 168:5989-5992.
31. Smiley ST, King JA, Hancock WW: Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. J Immunol 2001; 167:2887-2894.
32. Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, Chow JC, Strauss JF III: The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem 2001; 276:10229-10233.
33. Termeer C, Benedix F, Sleeman J, Fieber C, Voith U, Ahrens T, Miyake K, Freudenberg M, Galanos C, Simon JC: Oligosaccharides of Hyaluronan activate dendritic cells via toll-like receptor 4. J Exp Med 2002; 195:99-111.
34. Oppenheim JJ, Yang D: Alarmins: chemotactic activators of immune responses. Curr Opin Immunol 2005; 17:359-365.
35. Chen K, Huang J, Gong W, Iribarren P, Dunlop NM, Wang JM: Toll-like receptors in inflammation, infection and cancer. Int Immunopharmacol 2007; 7:1271-1285.
36. Akira S, Hoshino K: Myeloid differentiation factor 88-dependent and -independent pathways in toll-like receptor signaling. J Infect Dis 2003; 187(Suppl 2):S356-S363.
37. Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S: Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 2003; 301:640-643.
38. Takeuchi O, Hoshino K, Akira S: Cutting edge: TLR2-deficient and MyD88-deficient mice are highly susceptible to Staphylococcus aureus infection. J Immunol 2000; 165:5392-5396.
39. Klaffenbach D, Rascher W, Rollinghoff M, Dotsch J, Meissner U, Schnare M: Regulation and signal transduction of toll-like receptors in human chorioncarcinoma cell lines. Am J Reprod Immunol 2005; 53:77-84.
40. Mitsunari M, Yoshida S, Shoji T, Tsukihara S, Iwabe T, Harada T, Terakawa N: Macrophage-activating lipopeptide-2 induces cyclooxygenase-2 and prostaglandin E(2) via toll-like receptor 2 in human placental trophoblast cells. J Reprod Immunol 2006; 72:46-59.
41. Patni S, Wynen LP, Seager AL, Morgan G, White JO, Thornton CA: Expression and activity of Toll-like receptors 1-9 in the human term placenta and changes associated with labor at term. Biol Reprod 2009; 80:243-248.
42. Abrahams VM, Visintin I, Aldo PB, Guller S, Romero R, Mor G: A role for TLRs in the regulation of immune cell migration by first trimester trophoblast cells. J Immunol 2005; 175:8096-8104.
43. Abrahams VM, Bole-Aldo P, Kim YM, Straszewski-Chavez SL, Chaiworapongsa T, Romero R, Mor G: Divergent trophoblast responses to bacterial products mediated by TLRs. J Immunol 2004; 173:4286-4296.
44. Beijar EC, Mallard C, Powell TL: Expression and subcellular localization of TLR-4 in term and first trimester human placenta. Placenta 2006; 27:322-326.
45. Mor G, Romero R, Aldo PB, Abrahams VM: Is the trophoblast an immune regulator? The role of Toll-like receptors during pregnancy. Crit Rev Immunol 2005; 25:375-388.
46. Kumazaki K, Nakayama M, Yanagihara I, Suehara N, Wada Y: Immunohistochemical distribution of Toll-like receptor 4 in term and preterm human placentas from normal and complicated pregnancy including chorioamnionitis. Hum Pathol 2004; 35:47-54.
47. Ma Y, Krikun G, Abrahams VM, Mor G, Guller S: Cell type-specific expression and function of toll-like receptors 2 and 4 in human placenta: implications in fetal infection. Placenta 2007; 28:1024-1031.
48. Krikun G, Lockwood CJ, Abrahams VM, Mor G, Paidas M, Guller S: Expression of Toll-like receptors in the human decidua. Histol Histopathol 2007; 22:847-854.
49. Schatz F, Kayisli UA, Vatandaslar E, Ocak N, Guller S, Abrahams VM, Krikun G, Lockwood CJ: Toll-like receptor 4 expression in decidual cells and interstitial trophoblasts across human pregnancy. Am J Reprod Immunol 2012; 68:146-153.
50. Canavan TP, Simhan HN: Innate immune function of the human decidual cell at the maternal-fetal interface. J Reprod Immunol 2007; 74:46-52.
51. Adams KM, Lucas J, Kapur RP, Stevens AM: LPS induces translocation of TLR4 in amniotic epithelium. Placenta 2007; 28:477-481.
52. Dulay AT, Buhimschi CS, Zhao G, Oliver EA, Mbele A, Jing S, Buhimschi IA: Soluble TLR2 is present in human amniotic fluid and modulates the intraamniotic inflammatory response to infection. J Immunol 2009; 182:7244-7253.
53. Holmlund U, Cebers G, Dahlfors AR, Sandstedt B, Bremme K, Ekstrom ES, Scheynius A: Expression and regulation of the pattern recognition receptors Toll-like receptor-2 and Toll-like receptor-4 in the human placenta. Immunology 2002; 107:145-151.
54. Equils O, Lu D, Gatter M, Witkin SS, Bertolotto C, Arditi M, McGregor JA, Simmons CF, Hobel CJ: Chlamydia heat shock protein 60 induces trophoblast apoptosis through TLR4. J Immunol 2006; 177:1257-1263.
55. Chan G, Guilbert LJ: Ultraviolet-inactivated human cytomegalovirus induces placental syncytiotrophoblast apoptosis in a Toll-like receptor-2 and tumour necrosis factor-alpha dependent manner. J Pathol 2006; 210:111-120.
56. Abrahams VM, Aldo PB, Murphy SP, Visintin I, Koga K, Wilson G, Romero R, Sharma S, Mor G: TLR6 modulates first trimester trophoblast responses to peptidoglycan. J Immunol 2008; 180:6035-6043.
57. Mulla MJ, Myrtolli K, Tadesse S, Stanwood NL, Gariepy A, Guller S, Norwitz ER, Abrahams VM: Cutting-edge report: TLR10 plays a role in mediating bacterial peptidoglycan-induced trophoblast apoptosis. Am J Reprod Immunol 2013; 69:449-453.
58. Garg M, Potter JA, Abrahams VM: Identification of microRNAs that regulate TLR2-mediated trophoblast apoptosis and inhibition of IL-6 mRNA. PLoS ONE 2013; 8:e77249.
59. Kim YM, Romero R, Oh SY, Kim CJ, Kilburn BA, Armant DR, Nien JK, Gomez R, Mazor M, Saito S, Abrahams VM, Mor G: Toll-like receptor 4: a potential link between "danger signals", the innate immune system, and preeclampsia? Am J Obstet Gynecol 2005; 193:921-927.
60. Abrahams VM, Schaefer TM, Fahey JV, Visintin I, Wright JA, Aldo PB, Romero R, Wira CR, Mor G: Expression and secretion of antiviral factors by trophoblast cells following stimulation by the TLR-3 agonist, Poly(I: C). Hum Reprod 2006; 21:2432-2439.
61. 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; 152:4984-4992.
62. Koga K, Mor G: Toll-like receptors and pregnancy. Reprod Sci 2007; 14:297-299.
63. Kopriva SE, Chiasson VL, Mitchell BM, Chatterjee P: TLR3-induced placental miR-210 down-regulates the STAT6/interleukin-4 pathway. PLoS ONE 2013; 8:e67760.
64. Fest S, Aldo PB, Abrahams VM, Visintin I, Alvero A, Chen R, Chavez SL, Romero R, Mor G: Trophoblast-macrophage interactions: a regulatory network for the protection of pregnancy. Am J Reprod Immunol 2007; 57:55-66.
65. Wang H, Hirsch E: Bacterially-induced preterm labor and regulation of prostaglandin-metabolizing enzyme expression in mice: the role of toll-like receptor 4. Biol Reprod 2003; 69:1957-1963.
66. Elovitz MA, Wang Z, Chien EK, Rychlik DF, Phillippe M: A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4. Am J Pathol 2003; 163:2103-2111.
67. Rounioja S, Rasanen J, Ojaniemi M, Glumoff V, Autio-Harmainen H, Hallman M: Mechanism of acute fetal cardiovascular depression after maternal inflammatory challenge in mouse. Am J Pathol 2005; 166:1585-1592.
68. Li L, Kang J, Lei W: Role of Toll-like receptor 4 in inflammation-induced preterm delivery. Mol Hum Reprod 2010; 16:267-272.
69. Kajikawa S, Kaga N, Futamura Y, Kakinuma C, Shibutani Y: Lipoteichoic acid induces preterm delivery in mice. J Pharmacol Toxicol Methods 1998; 39:147-154.
70. Ilievski V, Lu SJ, Hirsch E: Activation of toll-like receptors 2 or 3 and preterm delivery in the mouse. Reprod Sci 2007; 14:315-320.
71. Murphy SP, Fast LD, Hanna NN, Sharma S: Uterine NK cells mediate inflammation-induced fetal demise in IL-10-null mice. J Immunol 2005; 175:4084-4090.
72. Koga K, Cardenas I, Aldo P, Abrahams VM, Peng B, Fill S, Romero R, Mor G: Activation of TLR3 in the trophoblast is associated with preterm delivery. Am J Reprod Immunol 2009; 61:196-212.
73. Thaxton JE, Romero R, Sharma S: TLR9 activation coupled to IL-10 deficiency induces adverse pregnancy outcomes. J Immunol 2009; 183:1144-1154.
74. Sun Y, Qin X, Shan B, Wang W, Zhu Q, Sharma S, Wu J, Lin Y: Differential effects of the CpG-Toll-like receptor 9 axis on pregnancy outcome in nonobese diabetic mice and wild-type controls. Fertil Steril 2013; 99:1759-1767.
75. Scharfe-Nugent A, Corr SC, Carpenter SB, Keogh L, Doyle B, Martin C, Fitzgerald KA, Daly S, O'Leary JJ, O'Neill LA: TLR9 provokes inflammation in response to fetal DNA: mechanism for fetal loss in preterm birth and preeclampsia. J Immunol 2012; 188:5706-5712.
76. Cardenas I, Mor G, Aldo P, Lang SM, Stabach P, Sharp A, Romero R, Mazaki-Tovi S, Gervasi M, Means RE: Placental viral infection sensitizes to endotoxin-induced pre-term labor: a double hit hypothesis. Am J Reprod Immunol 2011; 65:110-117.
77. Cardenas I, Means RE, Aldo P, Koga K, Lang SM, Booth CJ, Manzur A, Oyarzun E, Romero R, Mor G: Viral infection of the placenta leads to fetal inflammation and sensitization to bacterial products predisposing to preterm labor. J Immunol 2010; 185:1248-1257.
78. Ilievski V, Hirsch E: Synergy between viral and bacterial toll-like receptors leads to amplification of inflammatory responses and preterm labor in the mouse. Biol Reprod 2010; 83:767-773.
79. Jaiswal MK, Agrawal V, Mallers T, Gilman-Sachs A, Hirsch E, Beaman KD: Regulation of apoptosis and innate immune stimuli in inflammation-induced preterm labor. J Immunol 2013; 191:5702-5713.
80. Racicot K, Cardenas I, Wunsche V, Aldo P, Guller S, Means RE, Romero R, Mor G: Viral infection of the pregnant cervix predisposes to ascending bacterial infection. J Immunol 2013; 191:934-941.
81. Liu H, Redline RW, Han YW: Fusobacterium nucleatum induces fetal death in mice via stimulation of TLR4-mediated placental inflammatory response. J Immunol 2007; 179:2501-2508.
82. Adams Waldorf KM, Persing D, Novy MJ, Sadowsky DW, Gravett MG: Pretreatment with toll-like receptor 4 antagonist inhibits lipopolysaccharide-induced preterm uterine contractility, cytokines, and prostaglandins in rhesus monkeys. Reprod Sci 2008; 15:121-127.
83. Agrawal V, Smart K, Jilling T, Hirsch E: Surfactant protein (SP)-A suppresses preterm delivery and inflammation via TLR2. PLoS ONE 2013; 8:e63990.
84. Shimada S, Iwabuchi K, Watano K, Shimizu H, Yamada H, Minakami H, Onoe K: Expression of allograft inflammatory factor-1 in mouse uterus and poly(I:C)-induced fetal resorption. Am J Reprod Immunol 2003; 50:104-112.
85. Lin Y, Zeng Y, Di J, Zeng S: Murine CD200+ CK7+ trophoblasts in a poly (I:C)-induced embryo resorption model. Reproduction 2005; 130:529-537.
86. Lin Y, Liang Z, Chen Y, Zeng Y: TLR3-involved modulation of pregnancy tolerance in double-stranded RNA-stimulated NOD/SCID mice. J Immunol 2006; 176:4147-4154.
87. Lin Y, Zeng Y, Zeng S, Wang T: Potential role of toll-like receptor 3 in a murine model of polyinosinic-polycytidylic acid-induced embryo resorption. Fertil Steril 2006; 85(Suppl 1):1125-1129.
88. Zhang J, Wei H, Wu D, Tian Z: Toll-like receptor 3 agonist induces impairment of uterine vascular remodeling and fetal losses in CBA x DBA/2 mice. J Reprod Immunol 2007; 74:61-67.
89. Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW: A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol 1994; 171:158-164.
90. Tinsley JH, Chiasson VL, Mahajan A, Young KJ, Mitchell BM: Toll-like receptor 3 activation during pregnancy elicits preeclampsia-like symptoms in rats. Am J Hypertens 2009; 22:1314-1319.
91. Chatterjee P, Chiasson VL, Kopriva SE, Young KJ, Chatterjee V, Jones KA, Mitchell BM: Interleukin 10 deficiency exacerbates toll-like receptor 3-induced preeclampsia-like symptoms in mice. Hypertension 2011; 58:489-496.
92. Prince LS, Dieperink HI, Okoh VO, Fierro-Perez GA, Lallone RL: Toll-like receptor signaling inhibits structural development of the distal fetal mouse lung. Dev Dyn 2005; 233:553-561.
93. Hagberg H, Peebles D, Mallard C: Models of white matter injury: comparison of infectious, hypoxic-ischemic, and excitotoxic insults. Ment Retard Dev Disabil Res Rev 2002; 8:30-38.
94. Lee AJ, Lambermont VA, Pillow JJ, Polglase GR, Nitsos I, Newnham JP, Beilharz MW, Kallapur SG, Jobe AH, Kramer BW: Fetal responses to lipopolysaccharide-induced chorioamnionitis alter immune and airway responses in 7-week-old sheep. Am J Obstet Gynecol 2011; 204:e317-e324.
95. Shi L, Fatemi SH, Sidwell RW, Patterson PH: Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring. J Neurosci 2003; 23:297-302.
96. De Miranda J, Yaddanapudi K, Hornig M, Villar G, Serge R, Lipkin WI: Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances. MBio 2010; 1:1-10.
97. Patterson PH: Neuroscience. Maternal effects on schizophrenia risk. Science 2007; 318:576-577.
98. Ciaranello AL, Ciaranello RD: The neurobiology of infantile autism. Annu Rev Neurosci 1995; 18:101-128.
99. Gilmore JH, Jarskog LF, Vadlamudi S: Maternal poly I: C exposure during pregnancy regulates TNF alpha, BDNF, and NGF expression in neonatal brain and the maternal-fetal unit of the rat. J Neuroimmunol 2005; 159:106-112.
100. Stridh L, Mottahedin A, Johansson ME, Valdez RC, Northington F, Wang X, Mallard C: Toll-like receptor-3 activation increases the vulnerability of the neonatal brain to hypoxia-ischemia. J Neurosci 2013; 33:12041-12051.
101. Forrest CM, Khalil OS, Pisar M, Smith RA, Darlington LG, Stone TW: Prenatal activation of Toll-like receptors-3 by administration of the viral mimetic poly(I:C) changes synaptic proteins, N-methyl-D-aspartate receptors and neurogenesis markers in offspring. Mol Brain 2012; 5:22.
102. Clancy RM, Alvarez D, Komissarova E, Barrat FJ, Swartz J, Buyon JP: Ro60-associated single-stranded RNA links inflammation with fetal cardiac fibrosis via ligation of TLRs: a novel pathway to autoimmune-associated heart block. J Immunol 2010; 184:2148-2155.
103. Conrad ML, Ferstl R, Teich R, Brand S, Blumer N, Yildirim AO, Patrascan CC, Hanuszkiewicz A, Akira S, Wagner H, Holst O, von Mutius E, Pfefferle PI, Kirschning CJ, Garn H, Renz H: Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. J Exp Med 2009; 206:2869-2877.
104. Kim YM, Romero R, Chaiworapongsa T, Espinoza J, Mor G, Kim CJ: Dermatitis as a component of the fetal inflammatory response syndrome is associated with activation of Toll-like receptors in epidermal keratinocytes. Histopathology 2006; 49:506-514.
105. Lotz M, Gutle D, Walther S, Menard S, Bogdan C, Hornef MW: Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J Exp Med 2006; 203:973-984.
106. Manimtim WM, Hasday JD, Hester L, Fairchild KD, Lovchik JC, Viscardi RM: Ureaplasma urealyticum modulates endotoxin-induced cytokine release by human monocytes derived from preterm and term newborns and adults. Infect Immun 2001; 69:3906-3915.
107. Breen K, Brown A, Burd I, Chai J, Friedman A, Elovitz MA: TLR-4-dependent and -independent mechanisms of fetal brain injury in the setting of preterm birth. Reprod Sci 2012; 19:839-850.
108. Kim YM, Romero R, Chaiworapongsa T, Kim GJ, Kim MR, Kuivaniemi H, Tromp G, Espinoza J, Bujold E, Abrahams VM, Mor G: Toll-like receptor-2 and -4 in the chorioamniotic membranes in spontaneous labor at term and in preterm parturition that are associated with chorioamnionitis. Am J Obstet Gynecol 2004; 191:1346-1355.
109. Rindsjo E, Holmlund U, Sverremark-Ekstrom E, Papadogiannakis N, Scheynius A: Toll-like receptor-2 expression in normal and pathologic human placenta. Hum Pathol 2007; 38:468-473.
110. Kacerovsky M, Andrys C, Drahosova M, Musilova I, Hornychova H, Lesko D, Tosner J, Jacobsson B: Soluble Toll-like receptor 1 family members in the amniotic fluid of women with preterm prelabor rupture of the membranes. J Matern Fetal Neonatal Med 2012; 25:1699-1704.
111. Kacerovsky M, Andrys C, Hornychova H, Pliskova L, Lancz K, Musilova I, Drahosova M, Bolehovska R, Tambor V, Jacobsson B: Amniotic fluid soluble Toll-like receptor 4 in pregnancies complicated by preterm prelabor rupture of the membranes. J Matern Fetal Neonatal Med 2012; 25:1148-1155.
112. Zhang L, Yang H: Expression and localization of TLR4 and its negative regulator Tollip in the placenta of early-onset and late-onset preeclampsia. Hypertens Pregnancy 2012; 31:218-227.
113. Pineda A, Verdin-Teran SL, Camacho A, Moreno-Fierros L: Expression of toll-like receptor TLR-2, TLR-3, TLR-4 and TLR-9 is increased in placentas from patients with preeclampsia. Arch Med Res 2011; 42:382-391.
114. Wang X, Athayde N, Trudinger B: Placental vascular disease and toll-like receptor 4 gene expression. Am J Obstet Gynecol 2005; 192:961-966.
115. Chatterjee P, Weaver LE, Chiasson VL, Young KJ, Mitchell BM: Do double-stranded RNA receptors play a role in preeclampsia? Placenta 2011; 32:201-205.
116. Matzinger P: The danger model: a renewed sense of self. Science 2002; 296:301-305.
117. Wang B, Koga K, Osuga Y, Hirata T, Saito A, Yoshino O, Hirota Y, Harada M, Takemura Y, Fujii T, Taketani Y: High mobility group box 1 (HMGB1) levels in the placenta and in serum in preeclampsia. Am J Reprod Immunol 2011; 66:143-148.
118. Holmlund U, Wahamaa H, Bachmayer N, Bremme K, Sverremark-Ekstrom E, Palmblad K: The novel inflammatory cytokine high mobility group box protein 1 (HMGB1) is expressed by human term placenta. Immunology 2007; 122:430-437.
119. Mulla MJ, Brosens JJ, Chamley LW, Giles I, Pericleous C, Rahman A, Joyce SK, Panda B, Paidas MJ, Abrahams VM: Antiphospholipid antibodies induce a pro-inflammatory response in first trimester trophoblast via the TLR4/MyD88 pathway. Am J Reprod Immunol 2009; 62:96-111.
120. Bitner A, Sobala W, Kalinka J: Association between maternal and fetal TLR4 (896A>G, 1196C>T) gene polymorphisms and the risk of pre-term birth in the Polish population. Am J Reprod Immunol 2013; 69:272-280.
121. Krediet TG, Wiertsema SP, Vossers MJ, Hoeks SB, Fleer A, Ruven HJ, Rijkers GT: Toll-like receptor 2 polymorphism is associated with preterm birth. Pediatr Res 2007; 62:474-476.
122. Lorenz E, Hallman M, Marttila R, Haataja R, Schwartz DA: Association between the Asp299Gly polymorphisms in the Toll-like receptor 4 and premature births in the Finnish population. Pediatr Res 2002; 52:373-376.
123. Rey G, Skowronek F, Alciaturi J, Alonso J, Bertoni B, Sapiro R: Toll receptor 4 Asp299Gly polymorphism and its association with preterm birth and premature rupture of membranes in a South American population. Mol Hum Reprod 2008; 14:555-559.
124. Goepfert AR, Varner M, Ward K, Macpherson C, Klebanoff M, Goldenberg RL, Mercer B, Meis P, Iams J, Moawad A, Carey JC, Leveno K, Wapner R, Caritis SN, Miodovnik M, Sorokin Y, O'Sullivan MJ, Van Dorsten JP, Langer O: Differences in inflammatory cytokine and Toll-like receptor genes and bacterial vaginosis in pregnancy. Am J Obstet Gynecol 2005; 193:1478-1485.
125. Genc MR, Vardhana S, Delaney ML, Onderdonk A, Tuomala R, Norwitz E, Witkin SS: Relationship between a toll-like receptor-4 gene polymorphism, bacterial vaginosis-related flora and vaginal cytokine responses in pregnant women. Eur J Obstet Gynecol Reprod Biol 2004; 116:152-156.
126. van Rijn BB, Franx A, Steegers EA, de Groot CJ, Bertina RM, Pasterkamp G, Voorbij HA, Bruinse HW, Roest M: Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome. PLoS ONE 2008; 3:e1865.
127. Xie F, Turvey SE, Williams MA, Mor G, von Dadelszen P: Toll-like receptor signaling and pre-eclampsia. Am J Reprod Immunol 2010; 63:7-16.
128. Xie F, Hu Y, Speert DP, Turvey SE, Peng G, Money DM, Magee LA, von Dadelszen P; Toxaemia Study G: Toll-like receptor gene polymorphisms and preeclampsia risk: a case-control study and data synthesis. Hypertens Pregnancy 2010; 29:390-398.