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

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.