scholarly journals Involvement of Toll Like Receptor 2 Signaling in Secondary Injury during Experimental Diffuse Axonal Injury in Rats

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Yonglin Zhao ◽  
Junjie Zhao ◽  
Ming Zhang ◽  
Yahui Zhao ◽  
Jiaxi Li ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Axonal Injury ◽  
Diffuse Axonal Injury ◽  
Internal Capsule ◽  
Secondary Injury ◽  
Pathophysiological Mechanism ◽  
Toll Like Receptor ◽  
Tlr2 Expression ◽  
Mitogen Activated Protein ◽  
Toll Like Receptor 2

Treatment of diffuse axonal injury (DAI) remains challenging in clinical practice due to the unclear pathophysiological mechanism. Uncontrolled, excessive inflammation is one of the most recognized mechanisms that contribute to the secondary injury after DAI. Toll like receptor 2 (TLR2) is highlighted for the initiation of a vicious self-propagating inflammatory circle. However, the role and detailed mechanism of TLR2 in secondary injury is yet mostly unknown. In this study, we demonstrated the expression of TLR2 levels in cortex, corpus callosum, and internal capsule and the localization of TLR2 in neurons and glial cells in rat DAI models. Intracerebral knockdown of TLR2 significantly downregulated TLR2 expression, attenuated cortical apoptosis, lessened glial response, and reduced the secondary axonal and neuronal injury in the cortex by inhibiting phosphorylation of mitogen-activated protein kinases (MAPK) including Erk, JNK, and p38, translocation of NF-κB p65 from the cytoplasm to the nucleus, and decreasing levels of proinflammatory cytokines including interleukin-6, interleukin-1β, and tumor necrosis factor-α. On the contrary, administration of TLR2 agonist to DAI rats achieved an opposite effect. Collectively, we demonstrated that TLR2 was involved in mediating secondary injury after DAI by inducing inflammation via the MAPK and NF-κB pathways.

scholarly journals Inhibition of TLR4 Signalling-Induced Inflammation Attenuates Secondary Injury after Diffuse Axonal Injury in Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Yonglin Zhao ◽  
Yahui Zhao ◽  
Ming Zhang ◽  
Junjie Zhao ◽  
Xudong Ma ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Axonal Injury ◽  
Critical Role ◽  
Diffuse Axonal Injury ◽  
Adaptor Protein ◽  
Signalling Pathway ◽  
Inflammatory Factors ◽  
Secondary Injury ◽  
Neuroprotective Effects ◽  
Signalling Molecules

Increasing evidence suggests that secondary injury after diffuse axonal injury (DAI) damages more axons than the initial insult, but the underlying mechanisms of this phenomenon are not fully understood. Recent studies show that toll-like receptor 4 (TLR4) plays a critical role in promoting adaptive immune responses and have been shown to be associated with brain damage. The purpose of this study was to investigate the role of the TLR4 signalling pathway in secondary axonal injury in the cortices of DAI rats. TLR4 was mainly localized in microglial cells and neurons, and the levels of TLR4 downstream signalling molecules, including TLR4, myeloid differentiation primary response gene 88, toll/IR-1-(TIR-) domain-containing adaptor protein inducing interferon-beta, interferon regulatory factor 3, interferonβ, nuclear factorκB (NF-κB) p65, and phospho-NF-κB p65, significantly increased and peaked at 1 d after DAI. Inhibition of TLR4 by TAK-242 attenuated apoptosis, neuronal and axonal injury, and glial responses. The neuroprotective effects of TLR4 inhibition were associated with decreases in the levels of TLR4 downstream signalling molecules and inflammatory factors, including interleukin-1β, interleukin-6, and tumour necrosis factor-α. These results suggest that the TLR4 signalling pathway plays an important role in secondary injury and may be an important therapeutic target following DAI.

scholarly journals Essential role of IRAK-4 protein and its kinase activity in Toll-like receptor–mediated immune responses but not in TCR signaling

2007 ◽  
Vol 204 (5) ◽  
pp. 1013-1024 ◽  
Author(s):  
Tatsukata Kawagoe ◽  
Shintaro Sato ◽  
Andreas Jung ◽  
Masahiro Yamamoto ◽  
Kosuke Matsui ◽  
...  
Keyword(s):  
Immune Responses ◽  
Kinase Activity ◽  
Interleukin 1 ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Toll Like Receptor ◽  
Tcr Signaling ◽  
Mitogen Activated Protein

Interleukin-1 receptor–associated kinase 4 (IRAK-4) was reported to be essential for the Toll-like receptor (TLR)– and T cell receptor (TCR)–mediated signaling leading to the activation of nuclear factor κB (NF-κB). However, the importance of kinase activity of IRAK family members is unclear. In this study, we investigated the functional role of IRAK-4 activity in vivo by generating mice carrying a knockin mutation (KK213AA) that abrogates its kinase activity. IRAK-4KN/KN mice were highly resistant to TLR-induced shock response. The cytokine production in response to TLR ligands was severely impaired in IRAK-4KN/KN as well as IRAK-4−/− macrophages. The IRAK-4 activity was essential for the activation of signaling pathways leading to mitogen-activated protein kinases. TLR-induced IRAK-4/IRAK-1–dependent and –independent pathways were involved in early induction of NF-κB–regulated genes in response to TLR ligands such as tumor necrosis factor α and IκBζ. In contrast to a previous paper (Suzuki, N., S. Suzuki, D.G. Millar, M. Unno, H. Hara, T. Calzascia, S. Yamasaki, T. Yokosuka, N.J. Chen, A.R. Elford, et al. 2006. Science. 311:1927–1932), the TCR signaling was not impaired in IRAK-4−/− and IRAK-4KN/KN mice. Thus, the kinase activity of IRAK-4 is essential for the regulation of TLR-mediated innate immune responses.

scholarly journals Toll-Like Receptor 2 Expression as a New Hallmark of Advanced Endometriosis

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1813 ◽  
Author(s):  
Małgorzata Sobstyl ◽  
Paulina Niedźwiedzka-Rystwej ◽  
Ewelina Grywalska ◽  
Izabela Korona-Głowniak ◽  
Anna Sobstyl ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Lymphocytes ◽  
Characteristic Curve ◽  
Cost Effective ◽  
Peripheral Blood Lymphocytes ◽  
Toll Like Receptor ◽  
Myeloid Dendritic Cells ◽  
Tlr2 Expression ◽  
Toll Like Receptor 2 ◽  
Effective Diagnosis

Recent evidence suggests that immunological aspects play a pivotal role in this disorder. Toll-like receptor 2 (TLR2) is crucial in recognizing microbial infections and mediating innate immune response. The objective of our study was to rate with flow cytometry the levels of several subsets of dendritic cells, monocytes, and basic peripheral blood lymphocytes expressing TLR2, aiming at the determination of a possible correlation between the expression of TLR2 and the clinical outcomes of endometriosis in 40 patients and 40 age-matched healthy women. Our study showed the importance of TLR2 expression, mainly on myeloid dendritic cells (mDCs) and B cells in patients with endometriosis. Both mDCs BDCA1+CD19-TLR2+ and B lymphocytes CD19+TLR-2+ proved useful in the differentiation of affected individuals with stages 3–4 of the disease (area under the receiver operating characteristic curve /AUC/ = 0.96, p < 0.0001 for mDCs; AUC = 0.78, p = 0.0001 for B lymphocytes), and those presenting adhesion (AUC = 0.92, p < 0.0001 for mDCs; AUC = 0.82, p < 0.0001 for B lymphocytes) or infertility (AUC = 0.83, p < 0.0001 for mDCs; AUC = 0.73, p = 0.006 for B lymphocytes). Our findings suggest that the levels of TLR2-expressing cells, particularly mDCs and B lymphocytes, may be an effective biomarker of endometriosis, because the disease currently lacks clinically useful noninvasive biomarkers enabling early and cost-effective diagnosis.

scholarly journals Interleukin-1 Receptor but Not Toll-Like Receptor 2 Is Essential for MyD88-Dependent Th17 Immunity to Coccidioides Infection

2014 ◽  
Vol 82 (5) ◽  
pp. 2106-2114 ◽  
Author(s):  
Chiung-Yu Hung ◽  
María del Pilar Jiménez-Alzate ◽  
Angel Gonzalez ◽  
Marcel Wüthrich ◽  
Bruce S. Klein ◽  
...  
Keyword(s):  
Respiratory Disease ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Cell Activation ◽  
Pulmonary Infection ◽  
Interleukin 1 ◽  
Signal Pathways ◽  
Toll Like Receptor ◽  
Content Type ◽  
Toll Like Receptor 2

ABSTRACTInterleukin-17A (IL-17A)-producing CD4+T helper (Th17) cells have been shown to be essential for defense against pulmonary infection withCoccidioidesspecies. However, we have just begun to identify the required pattern recognition receptors and understand the signal pathways that lead to Th17 cell activation after fungal infection. We previously reported thatCard9−/−mice vaccinated with formalin-killed spherules failed to acquire resistance toCoccidioidesinfection. Here, we report that bothMyD88−/−andCard9−/−mice immunized with a live, attenuated vaccine also fail to acquire protective immunity to this respiratory disease. LikeCard9−/−mice, vaccinatedMyD88−/−mice revealed a significant reduction in numbers of both Th17 and Th1 cells in their lungs afterCoccidioidesinfection. Both Toll-like receptor 2 (TLR2) and IL-1 receptor type 1 (IL-1r1) upstream of MyD88 have been implicated in Th17 cell differentiation. Surprisingly, vaccinatedTLR2−/−and wild-type (WT) mice showed similar outcomes after pulmonary infection withCoccidioides, while vaccinatedIL-1r1−/−mice revealed a significant reduction in the number of Th17 cells in their infected lungs compared to WT mice. Thus, activation of both IL-1r1/MyD88- and Card9-mediated Th17 immunity is essential for protection againstCoccidioidesinfection. Our data also reveal that the numbers of Th17 cells were reduced inIL-1r1−/−mice to a lesser extent than inMyD88−/−mice, raising the possibility that other TLRs are involved in MyD88-dependent Th17 immunity to coccidioidomycosis. An antimicrobial action of Th17 cells is to promote early recruitment of neutrophils to infection sites. Our data revealed that neutrophils are required for vaccine immunity to this respiratory disease.

scholarly journals Toll-like Receptor 2 as a Marker Molecule of Advanced Ovarian Cancer

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1205
Author(s):  
Małgorzata Sobstyl ◽  
Paulina Niedźwiedzka-Rystwej ◽  
Rafał Hrynkiewicz ◽  
Dominika Bębnowska ◽  
Izabela Korona-Głowniak ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Advanced Ovarian Cancer ◽  
Screening Tests ◽  
Control Group ◽  
Newly Diagnosed ◽  
Toll Like Receptor ◽  
Tlr2 Expression ◽  
Diagnostic Approaches ◽  
Toll Like Receptor 2 ◽  
Marker Molecule

Ovarian cancer is a global problem that affects women of all ages. Due to the lack of effective screening tests and the usually asymptomatic course of the disease in the early stages, the diagnosis is too late, with the result that less than half of the patients diagnosed with ovarian cancer (OC) survive more than five years after their diagnosis. In this study, we examined the expression of TLR2 in the peripheral blood of 50 previously untreated patients with newly diagnosed OC at various stages of the disease using flow cytometry. The studies aimed at demonstrating the usefulness of TLR2 as a biomarker in the advanced stage of ovarian cancer. In this study, we showed that TLR2 expression levels were significantly higher in women with more advanced OC than in women in the control group. Our research sheds light on the prognostic potential of TLR2 in developing new diagnostic approaches and thus in increasing survival in patients with confirmed ovarian cancer.

scholarly journals Increasing toll-like receptor 2 on astrocytes induced by Schwann cell-derived exosomes promotes recovery by inhibiting CSPGs deposition after spinal cord injury

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Dayu Pan ◽  
Yongjin Li ◽  
Fuhan Yang ◽  
Zenghui Lv ◽  
Shibo Zhu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Schwann Cell ◽  
Western Blot ◽  
Signaling Pathway ◽  
Functional Recovery ◽  
Toll Like Receptor ◽  
Tlr2 Expression ◽  
Cord Injury ◽  
Toll Like Receptor 2

Abstract Background Traumatic spinal cord injury (SCI) is a severely disabling disease that leads to loss of sensation, motor, and autonomic function. As exosomes have great potential in diagnosis, prognosis, and treatment of SCI because of their ability to easily cross the blood–brain barrier, the function of Schwann cell-derived exosomes (SCDEs) is still largely unknown. Methods A T10 spinal cord contusion was established in adult female mice. SCDEs were injected into the tail veins of mice three times a week for 4 weeks after the induction of SCI, and the control group was injected with PBS. High-resolution transmission electron microscope and western blot were used to characterize the SCDEs. Toll-like receptor 2 (TLR2) expression on astrocytes, chondroitin sulfate proteoglycans (CSPGs) deposition and neurological function recovery were measured in the spinal cord tissues of each group by immunofluorescence staining of TLR2, GFAP, CS56, 5-HT, and β-III-tublin, respectively. TLR2f/f mice were crossed to the GFAP-Cre strain to generate astrocyte specific TLR2 knockout mice (TLR2−/−). Finally, western blot analysis was used to determine the expression of signaling proteins and IKKβ inhibitor SC-514 was used to validate the involved signaling pathway. Results Here, we found that TLR2 increased significantly on astrocytes post-SCI. SCDEs treatment can promote functional recovery and induce the expression of TLR2 on astrocytes accompanied with decreased CSPGs deposition. The specific knockout of TLR2 on astrocytes abolished the decreasing CSPGs deposition and neurological functional recovery post-SCI. In addition, the signaling pathway of NF-κB/PI3K involved in the TLR2 activation was validated by western blot. Furthermore, IKKβ inhibitor SC-514 was also used to validate this signaling pathway. Conclusion Thus, our results uncovered that SCDEs can promote functional recovery of mice post-SCI by decreasing the CSPGs deposition via increasing the TLR2 expression on astrocytes through NF-κB/PI3K signaling pathway.

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