Search

Toll-like receptors (TLRs) are a key family of pattern recognition receptors (PRRs) in the innate immune system. The activation of TLRs will not only prevent pathogen infection but also respond to damage-induced danger signaling. Increasing evidence suggests that TLRs play a critical role in breast cancer development and treatment. However, the activation of TLRs is a double-edged sword that can induce either pro-tumor activity or anti-tumor effect. The underlying mechanisms of these opposite effects of TLR signaling in cancer are not fully understood. Targeting TLRs is a promising strategy for improving breast cancer treatment, either as monotherapies or by improving other current therapies. Here we provide an update on the role of TLRs in breast cancer immunity and immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Zhang, Liu, DeRubeis and Zhang.)

Background: Toll-like receptors (TLRs) are the key sensors of innate immunity for triggering immune responses against infections. TLRs are well known to be expressed and activated in innate immune cells, such as macrophage and dendritic cells, but we and others have found that some TLRs are also functional in epithelial cells. However, the role of an epithelial TLR in prostate cancer remains elusive., Methods: TLR5 expression in messenger RNA and protein level in prostate cancer was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The activation of TLR5 signaling in epithelial cells was detected upon nuclear factor-κB activation by luciferase assay and western blot analysis, and proinflammatory cytokine activation by RT-qPCR. Distinguishing between the TLR5 and NLRC4 pathways, both recognizing flagellin, is determined by small interfering RNA and proinflammatory cytokine activation. The role of TLR5 in prostate cancer was analyzed by IHC and bioinformatics using a general and single-cell database., Results: In the present study, we show that TLR5, among other TLRs, is exceedingly expressed in human prostate cancer cells. This cancer epithelial cell TLR5 functions to activate the TLR5 signaling pathway in human prostate cancer cells, as it does with innate immune cell TLR5. The bacterial protein flagellin induces a robust immune response in prostate cancer cells in a TLR5-dependent but NLRC4-independent manner. TLR5 is highly expressed in prostate cancer patient specimens, and high TLR5 expression in prostate cancer patients indicates a favorable prognosis., Conclusions: TLR5, as an innate immunity receptor, is a functional TLR in human prostate cancer epithelial cells. TLR5 plays an important role in prostate cancer development and is a new potential prognosis biomarker. TLR5 may represent a novel immunotherapy target against prostate cancer., (© 2023 The Authors. The Prostate published by Wiley Periodicals LLC.)

Toll-like receptors (TLRs) recognize altered gut microbiota triggering an immune response. These responses play a critical role in the pathogenesis and treatment of inflammatory bowel disease (IBD). IBD is characterized by inflammation of the intestinal tracts as in Crohn's disease and ulcerative colitis. However, one challenge in determining the role of a specific TLR in IBD and its underlying mechanism is disparity. Variance in age, gender, race, and ethnicity shows a dramatic difference in the disease incidence, severity, and response to treatment. Delineating the role of TLRs in IBD relies on both a knockout mouse and a disease model. Here, we describe a detailed protocol on how to use nearly identical genetic backgrounds of TLR wild-type and knockout littermate mice in a dextran sodium sulfate (DSS)-induced colitis model., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Lung cancer is currently the leading cause of cancer-related deaths worldwide. Significant improvements in lung cancer therapeutics have relied on a better understanding of lung cancer immunity and the development of novel immunotherapies, as best exemplified by the introduction of PD-1/PD-L1-based therapies. However, this improvement is limited to lung cancer patients who respond to anti-PD-1 immunotherapy. Further improvements in immunotherapy may benefit from a better understanding of innate immune response mechanisms in the lung. Toll-like receptors (TLRs) are a key component of the innate immune response and mediate the early recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). TLR signaling modulates the tumor microenvironment from "cold" to "hot" leading to immune sensitization of tumor cells to treatments and improved patient prognosis. In addition, TLR signaling activates the adaptive immune response to improve the response to cancer immunotherapy through the regulation of anti-tumor T cell activity. This review will highlight recent progress in our understanding of the role of TLRs in lung cancer immunity and immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hoden, DeRubeis, Martinez-Moczygemba, Ramos and Zhang.)

KChIP proteins regulate Shal, Kv4.x, channel expression by binding to a conserved sequence at the N terminus of the subunit. The binding of KChIP facilitates a redistribution of Kv4 protein to the cell surface, producing a large increase in current along with significant changes in channel gating kinetics. Recently we have shown that mutants of Kv4.2 lacking the ability to bind an intersubunit Zn(2+) between their T1 domains fail to form functional channels because they are unable to assemble to tetramers and remain trapped in the endoplasmic reticulum. Here we find that KChIPs are capable of rescuing the function of Zn(2+) site mutants by driving the mutant subunits to assemble to tetramers. Thus, in addition to known trafficking effects, KChIPs play a direct role in subunit assembly by binding to monomeric subunits within the endoplasmic reticulum and promoting tetrameric channel assembly. Zn(2+)-less Kv4.2 channels expressed with KChIP3 demonstrate several distinct kinetic changes in channel gating, including a reduced time to peak and faster entry into the inactivated state as well as extending the time to recover from inactivation by 3-4 fold.

Voltage-gated potassium channels are formed by the tetramerization of their alpha subunits, in a process that is controlled by their conserved N-terminal T1 domains. The crystal structures of Shaker and Shaw T1 domains reveal interesting differences in structures that are contained within a highly conserved BTB/POZ domain fold. The most surprising difference is that the Shaw T1 domain contains an intersubunit Zn2+ ion that is lacking in the Shaker T1 domain. The Zn2+ coordination motif is conserved in other non-Shaker channels making this the most distinctive difference between these channels and Shaker. In this study we show that Zn2+ is an important co-factor for the tetramerization of isolated Shaw and Shal T1 domains. Addition of Zn2+ increases the amount of tetramer formed, whereas chelation of Zn2+ with phenanthroline blocks tetramerization and causes assembled tetramers to disassemble. Within an intact cell, full-length Shal subunits containing Zn2+ site mutations also fail to form functional channels, with the majority of the protein found to remain monomeric by size exclusion chromatography. Therefore, zinc-mediated tetramerization also is a physiologically important event for full-length functional channel formation.

The T1 domain, a highly conserved cytoplasmic portion at the N-terminus of the voltage-dependent K+ channel (Kv) alpha-subunit, is responsible for driving and regulating the tetramerization of the alpha-subunits. Here we report the identification of a set of mutations in the T1 domain that alter the gating properties of the Kv channel. Two mutants produce a leftward shift in the activation curve and slow the channel closing rate while a third mutation produces a rightward shift in the activation curve and speeds the channel closing rate. We have determined the crystal structures of T1 domains containing these mutations. Both of the leftward shifting mutants produce similar conformational changes in the putative membrane facing surface of the T1 domain. These results suggest that the structure of the T1 domain in this region is tightly coupled to the channel's gating states.

A 42 yr old male presented with left facial weakness. MRI showed lesions affecting the distal seventh nerve and third division of the trigeminal nerve. The seventh nerve was biopsied and showed a malignant epithelioid schwannoma. The patient underwent extensive resection followed by irradiation. This is one of very few examples of intracranial malignant peripheral nerve sheath tumors and the first reported example of an intracranial malignant epithelioid schwannoma. The literature is reviewed and completeness of resection appears to be the most pertinent prognostic factor.

Purpose: To define the natural history of post-Salmonella-infection reactive arthritis (ReA) in a point source cohort concurrently exposed to the same microorganism, and to determine any relationship between anti-Salmonella humoral immune response to the organism and clinical outcome at 5 years., Patients and Methods: A cohort of 423 Ontario Provincial Police officers with a clinical diagnosis of Salmonella food poisoning were defined in 1984. Five years following the food poisoning, a mail and telephone survey was carried out to determine all those who developed ReA within 3 months of the onset of dysentery. Medical and physiotherapy charts from an earlier study on the same cohort were incorporated. All patients with a history compatible with reactive arthritis were interviewed and examined. Serum was taken to determine the presence of isotypic antibodies to the lipopolysaccharide of the causative Salmonella typhimurium., Results: Twenty-seven of the 423 individuals with dysentery were identified as developing acute ReA. In one third of them, the arthritis resolved within 4 months of onset. Two thirds continued to have subjective complaints, mostly of minor significance. However, symptoms were severe enough to force a change in work for 4 patients. Another 4 patients had objective damage to joints radiographically. Objective changes to joints were documented on physical examination in 37% of ReA patients 5 years following onset of disease. IgA antilipopolysaccharide antibodies correlated with the severity and duration of disease. Tests of cellular immune function did not correlate with clinical variables., Conclusions: Chronic symptoms persist 5 years after the onset of ReA in the majority of patients. Joint damage by physical examination and radiographic assessment correlate with functional disability. Some early clinical features of disease, including prolonged diarrhea during the acute illness, may predict a worse outcome. IgA antilipopolysaccharides may serve as a disease marker for late post-Salmonella-infection ReA.