Faculty Opinions recommendation of Role of toll-like receptor 2 (TLR2) in neutrophil activation: GM-CSF enhances TLR2 expression and TLR2-mediated interleukin 8 responses in neutrophils.

Abstract Background Yersinia pestis, the etiological pathogen of plague, is capable of repressing the immune response of white blood cells to evade phagocytosis. The V-antigen (LcrV) was found to be involved in this process by binding to human Toll-like Receptor 2 (TLR2). The detailed mechanism behind this LcrV and TLR2 mediated immune response repression, however, is yet to be fully elucidated due to the lack of structural information. Results In this work, with protein structure modelling, we were able to construct a structure model of the heterotetramer of Y. pestis LcrV and human TLR2. Molecular dynamics simulation suggests the stability of this structure in aquatic environment. The LcrV model has a dumbbell-like structure with two globule domains (G1 at N-terminus and G2 away from membrane) connected with a coiled-coil linker (CCL) domain. The two horseshoe-shape TLR2 subunits form a V-shape structure, are not in direct contact with each other, and are held together by the LcrV homodimer. In this structure model, both the G1 and CCL domains are involved in the formation of LcrV homodimer, while all three domains are involved in LcrV-TLR2 binding. A mechanistic model was proposed based on this heterotetrameric structure model: The LcrV homodimer separates the TLR2 subunits to inhibit the dimerization of TLR2 and subsequent signal transfer for immune response; while LcrV could also inhibit the formation of heterodimers of TLR2 with other TLRs, and leads to immune response repression. Conclusions A heterotetrameric structure of Y. pestis LcrV and human TLR2 was modelled in this work. Analysis of this modelled structure showed its stability in aquatic environments and the role of LcrV domains and residues in protein-protein interaction. A mechanistic model for the role of LcrV in Y. pestis pathogenesis is raised based on this heterotetrameric structure model. This work provides a hypothesis of LcrV function, with which further experimental validation may elucidate the role of LcrV in human immune response repression.

Download Full-text

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

Cells ◽

10.3390/cells9081813 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1813 ◽

Cited By ~ 1

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.

Download Full-text