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Special Issue Information

Dear Colleagues,

Toll-like receptors (TLRs) are key innate pattern recognition receptors (PRRs) which recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). TLRs not only play a key role in host defense by recognizing PAMPs on microbes but also provide a strong link between infection, inflammation, and the development of autoimmunity. There is strong evidence that TLRs play a pivotal role in the promotion of inflammation without the presence of infection. TLRs play a non-redundant role in promoting tumor progression and recurrence in cancer, controlling immune responses that maintain gut homeostasis in inflammatory bowel disease, and promoting autoimmune kidney diseases such as Lupus Nephritis and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). In the context of autoimmunity, self-components released through excessive cell death act as DAMPS, inappropriately activating TLRs. The stimulation of TLRs via their cognate ligands recruits down-stream adaptor molecules. Once these adaptor molecules have been activated, signaling cascades culminate in the activation of transcription factors, such nuclear factor-kB (NFkB) interferons, mitogen-activated protein (MAP) kinases, and response factors (IRFs). These immune response genes induce the production of inflammatory cytokines and inflammation. This Special Issue aims to provide an overview of TLR activation and signaling in the context of non-infectious sterile inflammation and autoimmunity.

Dr. Kim M. O'Sullivan
Guest Editor

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Keywords

TLRs
PRRs
PAMPS
signaling adaptor molecules
inflammation

Published Papers (2 papers)

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Research

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15 pages, 1715 KiB

Open AccessArticle

Induction of Tertiary Phase Epileptiform Discharges after Postasphyxial Infusion of a Toll-Like Receptor 7 Agonist in Preterm Fetal Sheep

by Kenta H.T. Cho, Mhoyra Fraser, Bing Xu, Justin M. Dean, Alistair J. Gunn and Laura Bennet

Int. J. Mol. Sci. 2021, 22(12), 6593; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126593 - 19 Jun 2021

Cited by 4 | Viewed by 2051

Abstract

Background: Toll-like receptor (TLR) agonists are key immunomodulatory factors that can markedly ameliorate or exacerbate hypoxic–ischemic brain injury. We recently demonstrated that central infusion of the TLR7 agonist Gardiquimod (GDQ) following asphyxia was highly neuroprotective after 3 days but not 7 days of recovery. We hypothesize that this apparent transient neuroprotection is associated with modulation of seizure-genic processes and hemodynamic control. Methods: Fetuses received sham asphyxia or asphyxia induced by umbilical cord occlusion (20.9 ± 0.5 min) and were monitored continuously for 7 days. GDQ 3.34 mg or vehicle were infused intracerebroventricularly from 1 to 4 h after asphyxia. Results: GDQ infusion was associated with sustained moderate hypertension that resolved after 72 h recovery. Electrophysiologically, GDQ infusion was associated with reduced number and burden of postasphyxial seizures in the first 18 h of recovery (p < 0.05). Subsequently, GDQ was associated with induction of slow rhythmic epileptiform discharges (EDs) from 72 to 96 h of recovery (p < 0.05 vs asphyxia + vehicle). The total burden of EDs was associated with reduced numbers of neurons in the caudate nucleus (r² = 0.61, p < 0.05) and CA1/2 hippocampal region (r² = 0.66, p < 0.05). Conclusion: These data demonstrate that TLR7 activation by GDQ modulated blood pressure and suppressed seizures in the early phase of postasphyxial recovery, with subsequent prolonged induction of epileptiform activity. Speculatively, this may reflect delayed loss of early protection or contribute to differential neuronal survival in subcortical regions. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptor Signalling in Sterile Inflammation and Autoimmunity)

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Review

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19 pages, 1373 KiB

Open AccessReview

The Role of Toll-like Receptors (TLRs) Mediated Inflammation in Pancreatic Cancer Pathophysiology

by Arturo Orlacchio and Pellegrino Mazzone

Int. J. Mol. Sci. 2021, 22(23), 12743; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312743 - 25 Nov 2021

Cited by 19 | Viewed by 3603

Abstract

Pancreatic cancer (PC) is one of the most lethal forms of cancer, characterized by its aggressiveness and metastatic potential. Despite significant improvements in PC treatment and management, the complexity of the molecular pathways underlying its development has severely limited the available therapeutic opportunities. Toll-like receptors (TLRs) play a pivotal role in inflammation and immune response, as they are involved in pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Activation of TLRs initiates a signaling cascade, which in turn, leads to the transcription of several genes involved in inflammation and anti-microbial defense. TLRs are also deregulated in several cancers and can be used as prognostic markers and potential targets for cancer-targeted therapy. In this review we discuss the current knowledge about the role of TLRs in PC progression, focusing on the available TLRs-targeting compounds and their possible use in PC therapy. Full article

(This article belongs to the Special Issue The Role of Toll-Like Receptor Signalling in Sterile Inflammation and Autoimmunity)

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