Toll-Like Receptors and Their Potential Roles in Human Diseases

Topic Information

Dear Colleagues,

Toll-like receptors (TLRs) are an important family of transmembrane proteins. These immunoglycoproteins are known as pattern recognition receptors (PRRs). The intracellular and extracellular immunoglycoproteins of TLRs are activated via four types of different molecular patterns, including damage/danger-associated molecular patterns (DAMPs), microbial/microbe-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), and xenobiotic-associated molecular patterns (XAMPs). The activation of TLRs may lead to the induction of specific signaling pathways. TLRs resembling interleukins are involved in different immune responses and actively join the innate and adaptive immune systems in comprising a whole system. Moreover, TLRs similar to interleukins are expressed via immune and nonimmune cells. Indeed, interleukins together with TLRs have a pivotal role in the occurrence of interactions between immune and non¬immune cells under different conditions ranging from homeostasis to different types of diseases. The spectrum of diseases includes infectious diseases, autoimmune diseases, and cancers. Interestingly, TLRs and interleukins are the main proteins which contribute to the induction, reduction, or promotion of diseases. Depending on the type of disease and the physiological context, the expression of TLRs may decrease or increase. In other words, TLRs resembling interleukins can have antagonistic or synergistic effects on each other. Differences in TLR crosstalk are also observed depending on the different conditions. These features make TLR biomolecules unique and influential biomarkers. Molecular investigations have revealed that the occurrence of polymorphisms (e.g., single nucleotide polymorphisms (SNPs)) within TLR genes may lead to the development of autoimmune or infectious diseases and cancers. Because of the active roles of TLR biomolecules in homeostasis, diseases, and cancers, these glycoproteins are considered to have potential roles in human diseases and cancers. Due to this fact, TLRs may also be recognized as invaluable target molecules in therapeutics. This Topic will deeply explore the role of TLRs and their association with autoimmune and infectious diseases, cancers, and therapeutics. Review and original articles associated with any relevant fields of study are welcome. Potential topics include but are not limited to the following:

• Structural biology of toll-like receptors;
• Molecular biology of toll-like receptors;
• Bioinformatics of toll-like receptors;
• Toll-like receptors and infectious diseases;
• Toll-like receptors and autoimmune diseases;
• Toll-like receptors and tumorigenesis;
• Toll-like receptors and cancers;
• Toll-like receptors, ideal physiologic biomarkers;
• Single nucleotide polymorphisms, toll-like receptors, and infectious diseases;
• Single nucleotide polymorphisms, toll-like receptors, and autoimmune diseases;
• Single nucleotide polymorphisms, toll-like receptors, and cancers;
• Toll-like receptor therapeutics.

Dr. Payam Behzadi
Dr. Herney Andrés García-Perdomo
Dr. Márió Gajdács
Dr. Marina Pinheiro
Dr. Meysam Sarshar
Dr. Peter Magnusson
Dr. Marcos Roberto Tovani-Palone
Topic Editors

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Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biology biology	4.2	4.0	2012	18.7 Days	CHF 2700
Cancers cancers	5.2	7.4	2009	17.9 Days	CHF 2900
International Journal of Molecular Sciences ijms	5.6	7.8	2000	16.3 Days	CHF 2900

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Published Papers (6 papers)

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Open AccessArticle

L-Pampo™, a Novel TLR2/3 Agonist, Acts as a Potent Cancer Vaccine Adjuvant by Activating Draining Lymph Node Dendritic Cells

by Yoonki Heo, Eunbyeol Ko, Sejung Park, Si-On Park, Byung-Cheol Ahn, Jung-Sun Yum and Eunyoung Chun

Cancers 2023, 15(15), 3978; https://doi.org/10.3390/cancers15153978 - 04 Aug 2023

Cited by 1 | Viewed by 1190

Abstract

TLR agonists have emerged as an efficient cancer vaccine adjuvant system that induces robust immune responses. L-pampo™, a proprietary vaccine adjuvant of TLR2 and TLR3 agonists, promotes strong humoral and cellular immune responses against infectious diseases. In this study, we demonstrate that vaccines [...] Read more.

TLR agonists have emerged as an efficient cancer vaccine adjuvant system that induces robust immune responses. L-pampo™, a proprietary vaccine adjuvant of TLR2 and TLR3 agonists, promotes strong humoral and cellular immune responses against infectious diseases. In this study, we demonstrate that vaccines formulated with L-pampo™ affect the recruitment and activation of dendritic cells (DCs) in draining lymph nodes (dLNs) and leading to antigen-specific T-cell responses and anti-tumor efficacy. We analyzed DC maturation and T-cell proliferation using flow cytometry and ELISA. We determined the effect of L-pampo™ on DCs in dLNs and antigen-specific T-cell responses using flow cytometric analysis and the ELISPOT assay. We employed murine tumor models and analyzed the anti-tumor effect of L-pampo™. We found that L-pampo™ directly enhanced the maturation and cytokine production of DCs and, consequently, T-cell proliferation. OVA or OVA peptide formulated with L-pampo™ promoted DC migration into dLNs and increased activation markers and specific DC subsets within dLNs. In addition, vaccines admixed with L-pampo™ promoted antigen-specific T-cell responses and anti-tumor efficacy. Moreover, the combination of L-pampo™ with an immune checkpoint inhibitor synergistically improved the anti-tumor effect. This study suggests that L-pampo™ can be a potent cancer vaccine adjuvant and a suitable candidate for combination immunotherapy. Full article

(This article belongs to the Topic Toll-Like Receptors and Their Potential Roles in Human Diseases)

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14 pages, 1067 KiB  

Open AccessArticle

Potential Impact of Polymorphisms in Toll-like Receptors 2, 3, 4, 7, 9, miR-146a, miR-155, and miR-196a Genes on Osteoarthritis Susceptibility

by Debora Stefik, Vladimir Vranic, Nemanja Ivkovic, Gordana Velikic, Dusan M. Maric, Dzihan Abazovic, Danilo Vojvodic, Dusica L. Maric and Gordana Supic

Biology 2023, 12(3), 458; https://doi.org/10.3390/biology12030458 - 16 Mar 2023

Cited by 3 | Viewed by 1448

Abstract

Osteoarthritis (OA) is a progressive inflammatory disease of synovial joints and a leading cause of disability among adults. Inflammation-related genes, including genes for Toll-like receptors (TLRs), are tightly controlled by several microRNAs that, in addition to their pivotal role in the epigenetic regulation [...] Read more.

Osteoarthritis (OA) is a progressive inflammatory disease of synovial joints and a leading cause of disability among adults. Inflammation-related genes, including genes for Toll-like receptors (TLRs), are tightly controlled by several microRNAs that, in addition to their pivotal role in the epigenetic regulation of target genes, are ligands for TLR activation and downstream signaling. Thus, we evaluated the association between OA risk and genetic variants in TLR2, TLR3, TLR4, TLR7, TLR9, and microRNAs that regulate TLRs signaling miR146a, miR155, and miR196a2. Our study group consisted of 95 surgically treated OA patients and a control group of 104 healthy individuals. Genetic polymorphisms were determined using TaqMan real-time PCR assays (Applied Biosystems). Adjusted logistic regression analysis demonstrated that polymorphisms in TLR4 rs4986790 (OR = 2.964, p = 0.006), TLR4 rs4986791 (OR = 8.766, p = 0.00001), and TLR7 rs385389 (OR = 1.579, p = 0.012) increased OA risk, while miR-196a2 rs11614913 (OR = 0.619, p = 0.034) was significantly associated with decreased OA risk. Our findings indicate that polymorphisms in the TLR4 and TLR7 genes might increase OA risk and suggest a novel association of miR-196a2 polymorphism with decreased OA susceptibility. The modulation of TLRs and miRNAs and their cross-talk might be an attractive target for a personalized approach to OA management. Full article

(This article belongs to the Topic Toll-Like Receptors and Their Potential Roles in Human Diseases)

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16 pages, 5866 KiB  

Open AccessArticle

RNase 7 Inhibits Uropathogenic Escherichia coli-Induced Inflammation in Bladder Cells under a High-Glucose Environment by Regulating the JAK/STAT Signaling Pathway

by Chen-Hsun Ho, Pin-Wen Liao, Chia-Kwung Fan, Shih-Ping Liu and Po-Ching Cheng

Int. J. Mol. Sci. 2022, 23(9), 5156; https://doi.org/10.3390/ijms23095156 - 05 May 2022

Cited by 6 | Viewed by 1982

Abstract

Antimicrobial peptides (AMPs), which are natural antibiotics, protect against pathogens invading the urinary tract. RNase 7 with antimicrobial properties has rapid and powerful suppressive effects against Gram-positive and Gram-negative bacterial infections. However, its detailed antibacterial mechanisms have not been fully determined. Here, we [...] Read more.

Antimicrobial peptides (AMPs), which are natural antibiotics, protect against pathogens invading the urinary tract. RNase 7 with antimicrobial properties has rapid and powerful suppressive effects against Gram-positive and Gram-negative bacterial infections. However, its detailed antibacterial mechanisms have not been fully determined. Here, we investigate whether RNase 7 had an impact on bladder cells under uropathogenic Escherichia coli (UPEC) infection in a high-glucose environment using in vitro GFP-UPEC-infected bladder cell and PE-labeled TLR4, STAT1, and STAT3 models. We provide evidence of the suppressive effects of RNase 7 on UPEC infection and UPEC-induced inflammatory responses by regulating the JAK/STAT signaling pathway using JAK inhibitor and STAT inhibitor blocking experiments. Pretreatment with different concentrations of RNase 7 for 24 h concentration-dependently suppressed UPEC invasion in bladder cells (5 μg/mL reducing 45%; 25 μg/mL reducing 60%). The expressions of TLR4, STAT1, and STAT3 were also downregulated in a concentration-dependent manner after RNase 7 pretreatment (5 μg/mL reducing 35%, 54% and 35%; 25 μg/mL reducing 60%, 75% and 64%, respectively). RNase 7-induced decrease in UPEC infection in a high-glucose environment not only downregulated the expression of TLR4 protein and the JAK/STAT signaling pathway but also decreased UPEC-induced secretion of exogenous inflammatory IL-6 and IL-8 cytokines, although IL-8 levels increased in the 25 μg/mL RNase 7-treated group. Thus, inhibition of STAT affected pSTAT1, pSTAT3, and TLR4 expression, as well as proinflammatory IL-6 and IFN-γ expression. Notably, blocking JAK resulted in the rebound expression of related proteins, especially pSTAT1, TLR4, and IL-6. The present study showed the suppressive effects of RNase 7 on UPEC infection and induced inflammation in bladder epithelial cells in a high-glucose environment. RNase 7 may be an anti-inflammatory and anti-infective mediator in bladder cells by downregulating the JAK/STAT signaling pathway and may be beneficial in treating cystitis in DM patients. These results will help clarify the correlation between AMP production and UTI, identify the relationship between urinary tract infection and diabetes in UTI patients, and develop novel diagnostics or possible treatments targeting RNase 7. Full article

(This article belongs to the Topic Toll-Like Receptors and Their Potential Roles in Human Diseases)

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28 pages, 5601 KiB  

Open AccessArticle

Characterization of a Cutibacterium acnes Camp Factor 1-Related Peptide as a New TLR-2 Modulator in In Vitro and Ex Vivo Models of Inflammation

by Constance Mayslich, Philippe Alain Grange, Mathieu Castela, Anne Geneviève Marcelin, Vincent Calvez and Nicolas Dupin

Int. J. Mol. Sci. 2022, 23(9), 5065; https://doi.org/10.3390/ijms23095065 - 03 May 2022

Cited by 6 | Viewed by 3379

Abstract

Cutibacterium acnes (C. acnes) has been implicated in inflammatory acne where highly mutated Christie–Atkins–Munch–Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, we showed that CAMP1 production was independent of C. acnes phylotype and involved in [...] Read more.

Cutibacterium acnes (C. acnes) has been implicated in inflammatory acne where highly mutated Christie–Atkins–Munch–Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, we showed that CAMP1 production was independent of C. acnes phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and C. acnes. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as IL6, TNF, CXCL1, CXCL2, CXCL3, CXCL8, IL-1β, chemokine ligand (CCL)2, CCL4 and colony stimulating factor (CSF)2. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation. Full article

(This article belongs to the Topic Toll-Like Receptors and Their Potential Roles in Human Diseases)

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17 pages, 1499 KiB  

Open AccessReview

The Prognostic Role and Significance of Dll4 and Toll-like Receptors in Cancer Development

by Zacharias Fasoulakis, Antonios Koutras, Thomas Ntounis, Vasilios Pergialiotis, Athanasios Chionis, Alexandros Katrachouras, Vasileios-Chrysovalantis Palios, Panagiotis Symeonidis, Asimina Valsamaki, Athanasios Syllaios, Michail Diakosavvas, Kyveli Angelou, Athina A. Samara, Athanasios Pagkalos, Marianna Theodora, Dimitrios Schizas and Emmanuel N. Kontomanolis

Cancers 2022, 14(7), 1649; https://doi.org/10.3390/cancers14071649 - 24 Mar 2022

Cited by 4 | Viewed by 3050

Abstract

The Notch signaling pathway regulates the development of embryonic and tissue homeostasis of various types of cells. It also controls cell proliferation, variation, fate and cell death because it emits short-range messages to nearby cells. The pathway plays an important role in the [...] Read more.

The Notch signaling pathway regulates the development of embryonic and tissue homeostasis of various types of cells. It also controls cell proliferation, variation, fate and cell death because it emits short-range messages to nearby cells. The pathway plays an important role in the pathophysiology of various malignancies, controlling cancer creation. It also limits cancer development by adjusting preserved angiogenesis and cellular programs. One of the Notch signaling ligands (in mammals) is Delta-like ligand 4 (Dll4), which plays a significant role in the overall malignancies’ advancement. Particularly, sequencing Notch gene mutations, including those of Dll4, have been detected in many types of cancers portraying information on the growth of particular gynecological types of tumors. The current research article examines the background theory that implies the ability of Dll4 in the development of endometrial and other cancer types, and the probable therapeutic results of Dll4 inhibition. Full article

(This article belongs to the Topic Toll-Like Receptors and Their Potential Roles in Human Diseases)

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22 pages, 2728 KiB  

Open AccessReview

The Role of TLR2 in Infectious Diseases Caused by Mycobacteria: From Cell Biology to Therapeutic Target

by Wanbin Hu and Herman P. Spaink

Biology 2022, 11(2), 246; https://doi.org/10.3390/biology11020246 - 05 Feb 2022

Cited by 25 | Viewed by 5015

Abstract

Innate immunity is considered the first line of defense against microbial invasion, and its dysregulation can increase the susceptibility of hosts to infections by invading pathogens. Host cells rely on pattern recognition receptors (PRRs) to recognize invading pathogens and initiate protective innate immune [...] Read more.

Innate immunity is considered the first line of defense against microbial invasion, and its dysregulation can increase the susceptibility of hosts to infections by invading pathogens. Host cells rely on pattern recognition receptors (PRRs) to recognize invading pathogens and initiate protective innate immune responses. Toll-like receptor 2 (TLR2) is believed to be among the most important Toll-like receptors for defense against mycobacterial infection. TLR2 has been reported to have very broad functions in infectious diseases and also in other diseases, such as chronic and acute inflammatory diseases, cancers, and even metabolic disorders. However, TLR2 has an unclear dual role in both the activation and suppression of innate immune responses. Moreover, in some studies, the function of TLR2 was shown to be controversial, and therefore its role in several diseases is still inconclusive. Therefore, although TLR2 has been shown to have an important function in innate immunity, its usefulness as a therapeutic target in clinical application is still uncertain. In this literature review, we summarize the knowledge of the functions of TLR2 in host–mycobacterial interactions, discuss controversial results, and suggest possibilities for future research. Full article

(This article belongs to the Topic Toll-Like Receptors and Their Potential Roles in Human Diseases)

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