Toll-Like Receptor 2 is Involved in Abnormal Pregnancy in Mice Infected with Toxoplasma gondii During Late Pregnancy

Infection with Toxoplasma gondii during pregnancy causes failure of pregnancy maintenance, resulting in fetal death, abortion, stillbirth, or premature birth, but the mechanism of disease onset remains unclear. Although Toll-like receptor 2 (TLR2) is expressed on antigen-presenting cells and trophoblasts, the role of TLR2 in T. gondii infection during pregnancy is unknown. In this study, we investigated the role of TLR2 in congenital toxoplasmosis using TLR2-deficient (TLR2−/−) mice. T. gondii infection on gestational day 12.5 (Gd12.5) induced more abnormal pregnancy, including premature birth and stillbirth, in wild-type mice than in TLR2−/− mice. Multiple calcifications were observed in the placentas of the infected wild-type mice. At Gd18.5 (6days postinfection), the parasite numbers in the placenta and uterus and the histological changes did not differ significantly between the wild-type and TLR2−/− mice. However, T. gondii infection reduced the mRNA expression of interleukin-12p40 (IL-12p40) and increased IL-4 and IL-10 mRNAs in the placentas of the wild-type mice. In contrast, the placentas of the TLR2−/− mice showed no changes in the expression of these cytokines, including IL-6 and tumor necrosis factor α, in response to T. gondii infection. Serum interferon-γ levels were significantly lower in the infected TLR2−/− mice than in the infected wild-type mice on Gd18.5. Thus, the TLR2−/− mice were less susceptible to the induction of immune responses by T. gondii infection during late pregnancy. Therefore, TLR2 signaling may play a role in the development of disease states during pregnancy, specifically placental hypofunction.

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Abstract 169: Activation of the Phosphoinositide 3-Kinase/Akt Pathway is Responsible for Cardioprotection Induced by Modulation of TLR2

Circulation ◽

10.1161/circ.116.suppl_16.ii_11-c ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Chuanfu Li ◽

Fang Hua ◽

Tuanzhu Ha ◽

Jing Ma ◽

Jim Kelley ◽

...

Keyword(s):

Ischemic Injury ◽

Akt Signaling ◽

Toll Like Receptor ◽

Akt Signaling Pathway ◽

Wild Type ◽

Tlr2 Ligand ◽

Toll Like Receptor 2 ◽

Phosphoinositide 3 Kinase ◽

Dependent Mechanism

Activation of the phosphoinositide-3 kinase/Akt (PI3K/Akt) signaling pathway protects cells from ischemic injury. We have reported that the immune modulator, glucan, rapidly induces cardioprotection. Dectin-1 is a specific receptor for glucan and Toll-like receptor 2 (TLR2) is required for transmitting the signal from Dectin-1 into cells. However, the role of modulation of TLR2 in cardioprotection has not been investigated. We hypothesized that modulation of TLR2 will induce cardioprotection through a PI3K/Akt-dependent mechanism. To evaluate our hypothesis, we examined the effect of modulation of TLR2 on myocardial ischemic injury. TLR2 knockout (KO) (n=8) and wild type mice (n=8) were treated with glucan (1 mg/25g) or peptidoglycan (PDG, 75 μg/25g), a specific TLR2 ligand, one hr before the hearts were subjected to ischemia (1 hr)/reperfusion (4 hrs). Untreated mice (n=8) were also subjected to I/R. Myocardial infarction was determined by TTC staining. Infarct size was significantly reduced in glucan (11.6 ± 2.38% vs 36.1 ± 3.48%, p<0.01) and PDG (10.5 ± 3.03% vs 30.1 ± 7.59%, p<0.01) treated mice vs untreated mice. The levels of phospho-Akt (0.80 ± 0.10 vs 0.45 ± 0.09) and phospho-GSK3β (0.66 ± 0.14 vs 0.33 ± 0.10) were significantly increased in the myocardium of glucan treated mice compared with untreated mice. However, both glucan and PDG-induced cardioprotection were completely abolished in TLR2 KO mice. To investigate whether PI3K/Akt signaling is involved in cardioprotection induced by modulation of TLR2, we administered glucan (1 mg/25g) or PDG (75 μg/25g) to kdAkt (kinase deficient Akt) transgenic mice (n=8) one hr before myocardial I/R. Both glucan and PDG-induced cardioprotection were completely abolished in kdAkt mice. The results suggest that modulation of TLR2, either directly or indirectly, will induce cardioprotection through a PI3K/Akt dependent mechanism and that there is a critical link between TLR2 and PI3K/Akt signaling during myocardial I/R.

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CXCR3-dependent immune pathology in mice following infection with Toxoplasma gondii during early pregnancy

Infection and Immunity ◽

10.1128/iai.00253-20 ◽

2020 ◽

Author(s):

Akari Nishida ◽

Rina Ikeda ◽

Hidefumi Furuoka ◽

Yoshifumi Nishikawa

Keyword(s):

Toxoplasma Gondii ◽

Early Pregnancy ◽

Immune Cells ◽

Disease Onset ◽

Fetal Loss ◽

Congenital Toxoplasmosis ◽

Parasite Load ◽

Wild Type ◽

Immune Pathology ◽

Embryo Resorption

Toxoplasmosis is a worldwide zoonosis caused by the obligate intracellular parasite, Toxoplasma gondii. The symptoms of congenital toxoplasmosis range from embryonic death and resorption to subclinical infection, but the mechanism of disease onset remains unclear. The C-X-C motif chemokine receptor 3 (CXCR3) is highly expressed in Th1-associated immune cells and plays an important role in the trafficking and activation of immune cells. However, the roles of CXCR3 in T. gondii-induced fetal loss and the molecular mechanism of embryo resorption remain poorly understood. In this study, we investigated the role of CXCR3 in fetal wastage caused by T. gondii infection using CXCR3-deficient (CXCR3−/−) mice. CXCR3−/− and wild-type pregnant mice were inoculated intraperitoneally with T. gondii tachyzoites on day 3.5 of gestation (Gd3.5). Pregnancy rates decreased as the pregnancy progressed in both infected groups; however, infected CXCR3−/− mice showed a significant fetal loss at Gd13.5 compared with Gd7.5. All embryos of the infected groups showed necrosis, and embryo resorption was significantly increased in infected CXCR3−/− compared with wild-type mice at Gd13.5. The parasite load of fetoplacental tissues was significantly increased in CXCR3−/− mice at Gd10.5. Moreover, mRNA expression levels of inducible nitric oxide synthase were significantly increased in fetoplacental tissues from infected wild-type mice compared to infected CXCR3−/− mice following the infection. These results suggested that CXCR3-dependent immune responses provide anti-Toxoplasma activity and play an essential role in reducing embryo resorption and fetal loss caused by T. gondii infection during early pregnancy.

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An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2

10.1101/160432 ◽

2017 ◽

Author(s):

Rachel E. Miller ◽

Richard J. Miller ◽

Shingo Ishihara ◽

Phuong B. Tran ◽

Suzanne B. Golub ◽

...

Keyword(s):

Joint Pain ◽

Enzymatic Degradation ◽

Joint Damage ◽

Toll Like Receptor ◽

Wild Type ◽

Nociceptive Neurons ◽

Predominant Symptom ◽

Osteoarthritis Pain ◽

Toll Like Receptor 2

AbstractPain is the predominant symptom of osteoarthritis, but the connection between joint damage and the genesis of pain is not well understood. Loss of articular cartilage is a hallmark of osteoarthritis, and it occurs through enzymatic degradation of aggrecan by ADAMTS-4/5-mediated cleavage in the interglobular domain (E373-374 A). Further cleavage by MMPs (N341-342 F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We demonstrated that the 32-mer excites dorsal root ganglion (DRG) nociceptive neurons, both in culture and in intact explants. Treatment of cultured sensory neurons with the 32-mer induced them to express the pro-algesic chemokine, MCP-1/CCL2. These effects were mediated through Toll-like receptor (TLR)2, which we demonstrated was expressed by nociceptive neurons. In addition, intra-articular injection of the 32-mer provoked knee hyperalgesia in wild-type but not Tlr2 null mice. Blocking the production or action of the 32-mer in transgenic mice prevented the development of knee hyperalgesia in a murine model of osteoarthritis. These findings suggest that the aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors and is an important mediator of the development of osteoarthritis-associated joint pain.

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