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Host Response to Biomaterials
Published in Claudio Migliaresi, Antonella Motta, Scaffolds for Tissue Engineering, 2014
Sangeetha Srinivasan, Julia E. Babensee
TLRs are expressed on various cell types including DCs, MOs, T-cells, B-cells, fibroblasts, and ECs.56 TLRs have the ability to specifically recognize pathogen components or pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS), teichoic acids, lipoprotein, "double stranded" RNA (dsRNA), bacterial DNA, and flagellin.11'56,64 TLRs 1, 2, 4, 5, and 6 are expressed on the cell surface, while TLRs 3, 7, 8, and 9 are expressed on intracellular compartments, these receptors facilitate the internalization of antigen and trigger subsequent cellular responses.56 Crucial endogenous ligands of TLRs known as damage-associated molecular patterns (DAMPs) or "danger signals" initiate inflammatory responses upon cell death or tissue damage and act as natural adjuvants. Important DAMPs are endogenous molecules that are normally "hidden self" and released upon cell damage or tissue death such as high-mobility group box protein-1 (HMGB1), heat-shock proteins, and mRNA; or upon tissue damage such as heparan sulfate and fibrinogen.49 The ligation of intracellular TLRs leads to the downstream signaling of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and mitogen-activated protein kinase activation via a MyD88-dependent pathway.56,65 TLRs 3 and 4 can activate the transcription factor IFN regulating factor 3 in a MyD88-independent manner. This results in the generation of IFN-b and IFN-inducible gene products.66 NF-kB, also, participates in gene regulation in the MyD88-independent pathway of TLR signaling.11
Immunorecognition of Nucleic Acid Nanoparticles
Published in Peixuan Guo, Kirill A. Afonin, RNA Nanotechnology and Therapeutics, 2022
Jessica McMillan, M. Brittany Johnson
Toll-like receptors (TLRs), are important PRRs that are expressed on the cell surface and endosomal compartment to survey the extracellular and endosomal space for PAMPs and DAMPs (Botos, Segal, & Davies, 2011; Takeuchi & Akira, 2010). TLRs possess three highly conserved structural domains: a ligand-binding domain composed of leucine-rich repeats, a transmembrane domain, and a cytoplasmic signaling domain. Notably, TLRs are differentially expressed among cell types. For instance, plasmacytoid dendritic cells (pDCs) and B-cells readily express TLR7, while phagocytic cells such as monocytes, macrophages, and myeloid dendritic cells express TLR8 (Eng, Hsu, & Lin, 2018). In this section, we will focus on the endosomal TLRs, TLR3, TLR 7/8, and TLR9 that have been documented to recognize nucleic acids. Importantly, the ligands for these TLRs are characterized by composition (DNA, RNA, hybrid), strand length (base pairs), and other modifiers (unmethylated, analogs). TLR3 preferentially recognizes dsRNA that is 40–50bp in length (Leonard et al., 2008; Wang, Liu, Davies, & Segal, 2010). In contrast, TLR7/8 binds poly U or G/U-rich ssRNA, nucleoside analogs, and imidazoquinolines (Barbalat, Ewald, Mouchess, & Barton, 2011; Forsbach et al., 2008; Hornung et al., 2005). Finally, unmethylated CpG DNA that is a minimum of 20 nucleotides is recognized by TLR9 (Hemmi et al., 2000). Activation of TLR7/8 and 9 stimulates MyD88-dependent pathways while TLR3 stimulates toll/interleukin-1-receptor (TIR)- domain-containing adapter-inducing interferon-β (TRIF)-dependent production of interferons (IFNs) and pro-inflammatory cytokines (Kawasaki & Kawai, 2014).
Plasmonic Nanoparticles for Cancer Bioimaging, Diagnostics and Therapy
Published in Klaus D. Sattler, st Century Nanoscience – A Handbook, 2020
Bridget Crawford, Tuan Vo-Dinh
The GNS-mediated PTT can be used to activate the immune system and generate a synergistic effect by combining with anti-PD-L1 immunotherapy (Figure 18.5). For the SYMPHONY group, 80 mg/kg GNS was administrated through tail vein followed by laser treatment on the primary tumor but not for the distant tumor 24 h later. Anti-PD-L1 antibody was IP administrated after laser irradiation and every 3 days following until mice were tumor-free. On day 49, only SYMPHONY group mice survived. One of these mice was free of both primary and distant tumor and no tumor recurred in the following 3 months. The rechallenge was performed by injection of cancer cells and no tumor development occurred, suggesting a memory immunoresponse, or “cancer vaccine effect.” It was also observed that not only the laser treated primary tumor showed therapeutic response from SYMPHONY but the distant tumor was also treated. Immune cell phenotyping was performed to investigate immnuoresponse from SYMPHONY, and it was found that the combination treatment of GNS PTT and anti-PD-L1 significantly increased the percentage of total T cells, CD4, CD8 T cells and B cell. On the other hand, both the percentage and cell number of myeloid-derived suppressor cells (MDSCs) were significantly reduced in the combination treatment group. The efficacy of SYMPHONY relies on several synergistic processes. First, localized PTT with GNS and NIR irradiation kills primary tumor cells. Second, dying tumor cells release tumor-specific antigens and DAMPs, including heat shock proteins (HSPs). Third, DAMPs actively stimulate the immune response by modulating maturation, activation and presentation of antigen-presenting cells (APCs). Lastly, these activated APCs present tumor antigens to T cells, activating adaptive immunity. Therefore, blocking PD-L1/PD-1 signaling during T cell activation amplifies immune responses.
Understanding the complex microenvironment in oral cancer: the contribution of the Faculty of Dentistry, University of Otago over the last 100 years
Published in Journal of the Royal Society of New Zealand, 2020
Alison Mary Rich, Haizal Mohd Hussaini, Benedict Seo, Rosnah Bt Zain
How Tregs modulate the immune system is not fully understood but one way might be through TLR. TLR were first recognised on the surface of inflammatory cells, especially macrophages where they alert the body to external pathogens, particularly bacteria, and set off an immune response, but it is now well known that they recognise endogenous damage as well. Danger signals arising from injured or altered cells are known as damage–associated molecular patterns (DAMPS) and these are recognised by certain TLRs. Perhaps cancer cells and/or potentially malignant cells release DAMPS? Our group assessed 50 cases each of inflamed irritative hyperplasia (IH), epithelial dysplasia (ED) and OSCC and found that more inflammatory cells expressed TLR2 in the stroma of OSCC than in hyperplastic tissue (Figure 4A,B). No hyperplastic samples showed TLR2+ keratinocytes but keratinocytes in 64% of cases of OSCC were TLR2+. Positive TLR2 expression in the TME suggests that immune surveillance is activated against the altered epithelial cells while TLR2 expression by malignant keratinocytes may correlate with apoptosis resistance and hence the survival of tumour cells (Ng et al. 2011). Double immunofluoresence studies showed that TLR2+FoxP3+ Tregs were present in the OSCC microenvironment (Figure 5) with apparent cell-to-cell contact between TLR2+ and FoxP3+ cells. The presence of FoxP3+TLR2+ cells may represent a dendritic cell-dependent pathway capable of inhibiting Treg suppressive activity, potentially beneficial to the anti-tumour response (Hussaini et al. 2017).
Extraction of curcuminoids from Curcuma longa: comparative study between batch extraction and novel three phase partitioning
Published in Preparative Biochemistry and Biotechnology, 2019
Sujata S. Patil, Siddhant Bhasarkar, Virendra K. Rathod
The anti-inflammatory activity of the extract was studied by preventing heat denaturation of protein like albumin. Damage associated molecular patterns (DAMPs) are produced after protein denaturation which is due to damage to the tissue. Scavenging receptors (SRs) identifies these produced DAMPs. Both DAMPs and SRs together activate inflammatory mediators like cytokines spreading the inflammation further. For this, albumin which is a frequent skin protein was considered for denaturation of protein study. Therefore, the extent of inhibition of albumin denaturation is directly related to anti-inflammatory activity of the extract.