Diabetes and Inflammation
Awanish Kumar, Ashwini Kumar in Diabetes, 2020
Toll-like receptors (TLRs) belong to a special class of surface molecules, found on immune cells, which recognise pathogen-associated molecular pattern (PAMP) and were originally found to be involved in inflammatory reaction against pathogenic attack. These TLRs, as a result, induce innate immune responses. These receptors are also activated by exogenous and endogenous non-microbial ligands, such as fatty acids, resulting in the release of cytokines. The two major TLRs involved in inflammatory response are TLR-2 and TLR-4. Some exogenous and endogenous ligands for these receptors are high mobility group B1 (HMGB1), necrotic cells, hyaluronic acid fragments, serum amyloid A (SAA) and advanced glycation end products (AGEs). These two TLRs are the most important among this family of receptors which play a very important inflammatory role in the development of atherosclerosis. Their expression is also seen to be increased dramatically in macrophages involved in the development of foam cells in atherosclerosis. TLR-2 and TLR-4 expression, their downstream signalling and inflammation are seen to be positively correlated with HbA1c levels in type 1 diabetic (T1DM) subjects [6,23].
Structure and function of the mesothelial cell
Wim P. Ceelen, Edward A. Levine in Intraperitoneal Cancer Therapy, 2015
Toll-like receptors (TLRs), nucleotide-binding oligomerization domain–like receptors, RIG-I-like receptors, and C-type lectin-like receptors bind to microorganisms such as bacteria, fungi, and viruses [44,45]. Mesothelial cells constitutively express TLR1-6 mRNA. TLR2 recognizes numerous microbial molecules such as Gram-positive bacteria and is upregulated in response to proinflammatory cytokines including IFN-γ, TNF-α, and IL-1β [46–48]. TLR4 responds to Gram-negative bacteria through recognition of LPS [49] and is upregulated by Angiotensin II [50]. Human mesothelial cells also express TLR3 and other viral receptors RIG-1 and MDA5, which recognize viral double-stranded RNA and are also upregulated following stimulation with IFN-γ, TNF-α, and IL-1β [51]. TLR3 induces upregulation of MMP-9 and tissue inhibitor of MMP (TIMP)-1 [52] as well as IFN-inducible protein 10 (IP-10) in mesothelial cells. IP-10 is also upregulated by IFN-α, IFN-β, and IFN-γ [53]. Upregulation of early response genes by bacterial infection of mesothelial cells may contribute to mesothelial cell apoptosis.
Parasite Versus Host: Pathology and Disease
Eric S. Loker, Bruce V. Hofkin in Parasitology, 2023
Hemozoin’s toxic effect may be in part due to the fact that following its release from lysed erythrocytes, it is ingested by macrophages and other phagocytes. Because hemozoin cannot be efficiently degraded within the phagocyte’s endomembrane system, further phagocytosis is impeded. At least part of hemozoin’s effect, however, may be more indirect and be better understood as immunopathology: pathology caused by an overzealous or otherwise damaging immune response. Hemozoin is known to form complexes with other parasite-derived molecules, including Plasmodium DNA. These complexes may then bind specific Toll-like receptors on the surface of phagocytes. The subsequent signal transduction results in an inflammatory response via an up-regulation of the cytokines IL-12 and TNFα.
Small molecule agonists of toll-like receptors 7 and 8: a patent review 2014 – 2020
Published in Expert Opinion on Therapeutic Patents, 2020
Madeleine E. Kieffer, Akash M. Patel, Scott A. Hollingsworth, W. Michael Seganish
Toll-like receptors have long been implicated in both the cause and potential treatment of diseases due to their role in inflammatory pathways and innate immune activation. For instance, genome-wide association studies have shown correlations of single nucleotide polymorphisms with vulnerability to both viral and inflammatory diseases [20]. Over-stimulation of TLRs is implicated in inflammatory and autoimmune-related disorders including systemic lupus erythematosus, sepsis, and atherosclerosis [21]. However, agonism of the TLRs has also been shown to be beneficial in disease states such as cancer and infectious diseases. As such, the ability to modulate the TLR7/8 inflammatory response has profound implications in therapeutic discovery. Specifically, the development of small molecule agonists to harness this inflammatory pathway provides a potential path toward the treatment of multiple diseases. As an example, the TLR7/8 agonist, imiquimod, has been approved for the treatment of genital warts, actinic keratosis, and non-melanoma skin cancers [22]. Although limited to topical administration due to safety concerns with systemic dosing, this early approval illustrates the potential of small molecule agonists and has motivated current efforts.
MyD88 as a therapeutic target for inflammatory lung diseases
Published in Expert Opinion on Therapeutic Targets, 2018
Franco Di Padova, Valerie F. J. Quesniaux, Bernhard Ryffel
The innate immune system senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In mammals there are more than 10 members of the toll-like receptors (TLR) that recognize conserved components of microorganisms and pathogens [1]. Activation of the TLRs leads not only to the induction of innate inflammatory responses, but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory responses are dependent on a common signaling pathway that is mediated by the adaptor protein myeloid differentiation factor 88 (MyD88), which associates with the TIRAP and activates a pro-inflammatory cascade [2]. Besides MyD88 TLR3 activates the TRIF/TRAM pathway which have reviewed before [3]. The MyD88 adaptor protein is not limited to TLRs, but is also involved in the signaling of IL-1R family members such as IL-1R1, IL-18R, IL-33R/IL-33R and IL-36R [4,5]. MyD88 is broadly distributed in the tissues and is involved in signals activating TLR and IL-1R family members in response to microbes and injury. In Figure 1 shows the association of MyD88 with the IL-1 receptor family members, which has been reviewed recently [5–7].
Immunomodulatory role of recombinant human erythropoietin in acute kidney injury induced by crush syndrome via inhibition of the TLR4/NF-κB signaling pathway in macrophages
Published in Immunopharmacology and Immunotoxicology, 2020
Jiaojiao Zhou, Yajun Bai, Yong Jiang, Padamata Tarun, Yuying Feng, Rongshuang Huang, Ping Fu
Toll-like receptors (TLRs) can identify pathogen-associated molecular patterns (PAMPs) and initiate immune responses against invading pathogens, concurrently shaping the subsequent adaptive immune response. TLRs are expressed in many cell types, including dendritic cells, endothelia, epithelial cells, monocytes, and macrophages. TLR4 is closely related with immune inflammatory response, apoptosis, regeneration, and repair in AKI [25,26]. TLR4 expression in renal tubular epithelial cell is upregulated in renal tissue of ischemia-reperfusion rats [27]. The individual role of TLR4 in IR was established by Pulskens et al., who reported that TLR4 exerts pro-inflammatory effects by decreasing the number of infiltrating granulocytes and chemokines and ameliorating renal function in the kidneys of TLR4−/− mice [28].
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