Abstract
On microbial invasion, the host immediately evokes innate immune responses. Recent studies have demonstrated that Toll-like receptors (TLRs) play crucial roles in innate responses that lead not only to the clearance of pathogens but also to the efficient establishment of acquired immunity by directly detecting molecules from microbes. In terms of intracellular TLR-mediated signaling pathways, cytoplasmic adaptor molecules containing Toll/IL-1R (TIR) domains play important roles in inflammatory immune responses through the production of proinflammatory cytokines, nitric oxide, and type I interferon, and upregulation of costimulatory molecules. In this paper, we will describe our current understanding of the relationship between TLRs and their ligands derived from pathogens such as viruses, bacteria, fungi, and parasites. Moreover, we will review the historical and current literature to describe the mechanisms behind TLR-mediated activation of innate immune responses.
Highlights
Innate and adaptive immunities play important roles in the elimination of various pathogens such as viruses, bacteria, and parasites in mammals [1,2,3]
TLR3 recognizes a synthetic double-stranded RNA analog, polyinosinicpolycytidylic acid, and dsRNA derived from Reovirus, EMCV, RSV, or West Nile virus (WNV) [1]
A very recent study demonstrates a two-stage activation mechanism for TLR4-mediated signaling pathways, in which assembly of a multiprotein complex including MyD88, TRAF6, Ubc13, IKKγ, cIAP1/2, TAK1, and TRAF3 induces K63-linked ubiquitination of cIAP1/2 that leads to degradation of TRAF3, subsequently resulting in MyD88-signaling complex inducing its translocation from membrane to the cytosol and TAK1 activation [70]
Summary
Innate and adaptive immunities play important roles in the elimination of various pathogens such as viruses, bacteria, and parasites in mammals [1,2,3]. The adaptive immune system exerts highly specific responses to microbes by producing antibodies from B cells or through the generation of killer or helper T lymphocytes, resulting in life-long immunological memory. This process may take weeks, or even months, to establish sufficient levels of immunity. Almost 20 years ago, Janeway proposed that pattern recognition receptors (PRRs), which recognize pathogenassociated molecular patterns (PAMPs) specific to each pathogen, are expressed on innate immune cells and discriminate self or nonself structures [4]. Similar to Drosophila Toll signaling and mammalian IL-1R signaling, TLR signaling activates NF-κB as well as mitogen-activated protein kinases (MAPKs) to stimulate gene expression, including proinflammatory cytokines and costimulatory molecules [9]. We will discuss the current view of mammalian TLR pathways, focusing on the molecular basis of extracellular and intracellular signaling events
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