ISBN 978-93-91882-59-4 (Print)
ISBN 978-93-91882-60-0 (eBook)
DOI: 10.9734/bpi/mono/978-93-91882-59-4

Innate immunity is the first-line host defense mechanism that operates to protect animals (vertebrates and invertebrates) from infectious microorganisms. As such, it plays a critical role in containing most inflammatory processes. In addition, molecules induced during the innate immune response, including cytokines and costimulatory molecules, play a critical role in the induction of the adaptive immune response in mammals. Mammalian toll-like receptors (TLRs)are members ofthe pattern-recognition receptor family and playa central role in the initiation of innate cellular immuneresponses and the subsequent adaptive immune responses.Toll-like receptors inflammatory pathways may be related to number of diseases such as clinical depression, gastrointestinal tract inflammatory diseases and cardiovascular disorders. This book has been written with the basic concept oftoll-like receptors and their potential signaling pathways in inflammatory diseases. Toll-like receptors owe their names to a famousDrosophila gene, Toll. It was usedin the early 1980s by C. Nu¨sslein-Volhard to qualify thephenotype of a new mutant discovered in her pioneeringmutagenesis screen to dissect the genetic pathways controllingembryonic development in the fruit fly Drosophilamelanogaster.Toll-like receptors are protective immune sentriesthat sense pathogen-associated molecular patternssuch as unmethylated double-stranded DNA, single-stranded RNA, lipoproteins, lipopolysaccharide, and flagellin. In innate immunemyeloid cells, TLRs induce the secretion of inflammatorycytokines, thereby engaging lymphocytesto mount an adaptive, antigen-specific immuneresponse.Individual TLRs differentially recruit members of a set of Toll/interleukin 1 receptor(TIR) domain-containingadaptorssuchasMyeloid differentiation primary response 88 (MyD88),TIR-domain-containing adapter-inducing interferon-\(\beta\) (TRIF),TIR-containing adaptor protein (Tirap), also named MyD88 adaptor-like protein (TIRAP/MAL), orTRAM.MyD88isutilizedbyallTLRsandactivatesnuclear factor kappa-light-chain-enhancer of activated B cells) NF-kB(andmitogen-activated protein kinase) MAPKs (fortheinductionofinflammatorycytokinegenes.Toll receptors play detrimental role in cardiovascular disease like ischemia-reperfusion injury (IRI),atherosclerosis,Diabetic nephropathy,Gastrointestinal (GIT) disorders likeInflammatory bowel disease (IBD) and Helicobacter pylori (H. pylori), Brain diseases like (Neurodegenerative conditions such as Alzheimer’s disease), and Cancer.


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Contents


Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases

Najah R. Hadi, Saad Rasool Shaker, Nada R. Alharis

Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases, 23 August 2021, Page 1
https://doi.org/10.9734/bpi/mono/978-93-91882-59-4/CH0

Toll-like receptors (TLRs) are an important family of receptors that constitute the first line of defense system against microbes. They can recognize both invading pathogens and endogenous danger molecules released from dying cells and damaged tissues and play a key role in linking innate and adaptive immunity. TLRs are widely distributed in both immune and other body cells. The expressions and locations of TLRs are regulated in response to specific molecules derived from pathogens or damaged host cells. The binding of ligands to TLR activates specific intracellular signaling cascades that initiate host defense reactions. Recent studies have shown that gastrointestinal epithelial cells express almost all TLR subtypes characterized to date and that the expression and activation of TLRs in the GI tract are tightly and coordinately regulated. Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous luminal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system.  Gastric epithelial cells represent the first line of innate immune defence against H. pylori, and respond to infection by initiating numerous cell signalling cascades, resulting in cytokine induction and the subsequent recruitment of inflammatory cells to the gastric mucosa. Pathogen recognition receptors of the Toll-like receptor (TLR) family mediate many of these cell signalling events. Engagement of toll-like receptors on immune and resident vascular cells can affect atherogenesis as signalling downstream of these receptors can elicit proinflammatory cytokine release, lipid uptake, and foam cell formation and activate cells of the adaptive immune system. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy).  The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established. An important contributor to microglial activation is toll-like receptor 4, a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli.

Toll-like Receptors in Innate Immunity

Najah R. Hadi, Saad Rasool Shaker, Nada R Alharis

Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases, 23 August 2021, Page 2-25
https://doi.org/10.9734/bpi/mono/978-93-91882-59-4/CH1

Innate immunity is present in both vertebrates and invertebrates, raising the possibility that investigation of host defense mechanisms in model organisms prone to genetic analysis, such as the fruit fly Drosophila, may shed light on the nature of the elusive Pattern Recognition Receptors. The family of Toll-like receptors plays an essential role in the induction of the immune response. These receptors sense the presence of microbial ligands and activate the nuclear factor-_B transcription factor. The name of Toll-like receptors comes from the vernacular German Toll, meaning super or fantastic. Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity.

Toll-like Receptor Signaling Pathways

Najah R. Hadi, Saad Rasool Shaker, Nada R Alharis

Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases, 23 August 2021, Page 26-44
https://doi.org/10.9734/bpi/mono/978-93-91882-59-4/CH2

Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-kB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. The main players in innate immunity are phagocytes such as neutrophils, macrophages, and dendritic cells. These cells can discriminate between pathogens and self by utilizing signals from the Toll-like receptors (TLRs)1. TLRs recognize conserved motifs predominantly found in microorganisms but not in vertebrates. Stimulation of TLRs causes an immediate defensive response, including the production of an array of antimicrobial peptides and cytokines. Accumulating evidence has shown that individual TLRs can activate overlapping as well as distinct signaling pathways, ultimately giving rise to distinct biological effects.

Role of Toll-like Receptors in Health and Diseases of Gastrointestinal Tract

Najah R. Hadi, Saad Rasool Shaker, Nada R Alharis

Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases, 23 August 2021, Page 45-74
https://doi.org/10.9734/bpi/mono/978-93-91882-59-4/CH3

The human gastrointestinal (GI) tract is colonized by non-pathogenic commensal microflora and frequently exposed to many pathogenic organisms. For the maintenance of GI homeostasis, the host must discriminate between pathogenic and non-pathogenic organisms and initiate effective and appropriate immune and inflammatory responses. Mammalian toll-like receptors (TLRs) are members of the pattern recognition receptor (PRR) family that plays a central role in the initiation of innate cellular immune responses and the subsequent adaptive immune responses to microbial pathogens. Recent studies have shown that gastrointestinal epithelial cells express almost all TLR subtypes characterized to date and that the expression and activation of TLRs in the GI tract are tightly and coordinately regulated. Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous luminal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system.  Gastric epithelial cells represent the first line of innate immune defence against H. pylori, and respond to infection by initiating numerous cell signalling cascades, resulting in cytokine induction and the subsequent recruitment of inflammatory cells to the gastric mucosa. Pathogen recognition receptors of the Toll-like receptor (TLR) family mediate many of these cell signalling events.

Emerging Role of Toll-like Receptors in Atherosclerosis

Najah R. Hadi, Saad Rasool Shaker, Nada R Alharis

Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases, 23 August 2021, Page 75-93
https://doi.org/10.9734/bpi/mono/978-93-91882-59-4/CH4

Atherosclerosis, the leading cause of cardiovascular disease (CVD), is driven by inflammation. Increasing evidence suggests that toll-like receptors (TLRs) are key orchestrators of the atherosclerotic disease process. Interestingly, a distinct picture is being revealed for individual receptors in atherosclerosis. TLRs exhibit a complex nature enabling the detection of multiple motifs named danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Activation of these receptors triggers an intracellular signalling cascade mediated through MyD88 or TRIF, leading to the production of pro- and anti-inflammatory cytokines. Inflammation drives atherosclerosis. Both immune and resident vascular cell types are involved in the development of atherosclerotic lesions. The phenotype and function of these cells are key in determining the development of lesions. Toll-like receptors are the most characterised innate immune receptors and are responsible for the recognition of exogenous conserved motifs on pathogens, and, potentially, some endogenous molecules. Both endogenous and exogenous TLR agonists may be present in atherosclerotic plaques. Engagement of toll-like receptors on immune and resident vascular cells can affect atherogenesis as signalling downstream of these receptors can elicit proinflammatory cytokine release, lipid uptake, and foam cell formation and activate cells of the adaptive immune system.

Signaling Danger: Toll-Like Receptors and Their Potential Roles in Diseases

Najah R. Hadi, Saad Rasool Shaker, Nada R Alharis

Important Aspects of Toll-like Receptors: Signaling Pathways in Diseases, 23 August 2021, Page 94-113
https://doi.org/10.9734/bpi/mono/978-93-91882-59-4/CH5

Toll-like receptors (TLR) are an emerging family of receptors that recognize pathogen-associated molecular patterns and promote the activation of leukocytes and intrinsic renal cells. Ligands of the TLR include exogenous microbial components such as LPS (TLR4), lipoproteins and peptidoglycans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral unmethylated cytosin-guanosin dinucleotide (CpG)-DNA (TLR9), and endogenous molecules including heat-shock proteins and extracellular matrix molecules. Upon stimulation, TLR induce expression of inflammatory cytokines or costimulatory molecules via the MyD88-dependent and MyD88-independent signaling pathways shared with the interleukin-1 receptors. TLR are differentially expressed on leukocyte subsets and non-immune cells and appear to regulate important aspects of innate and adaptive immune responses. Tubular epithelial cells are among the non-immune cells that express TLR1, -2, -3, -4, and -6, suggesting that these TLR might contribute to the activation of immune responses in tubulointerstitial injury (e.g., bacterial pyelonephritis, sepsis, and transplant nephropathy).  The role of Toll-like receptors as a primary part of our microbe defense system has been shown in several studies, but their possible function as mediators in allergy and asthma remains to be established.  An important contributor to microglial activation is toll-like receptor 4, a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli.