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Toll-like Receptors

Inflammation

Inflammation is the first response of the immune system to tissue damage. If the inflammation is short-lasting (lasting only a few days) it is referred to as an acute inflammation. Prolonged inflammation results in chronic inflammation like rheumatoid arthritis and atherosclerosis. When infection (bacterial or viral) occurs the innate immune response kicks in and triggers the release of pro-inflammatory cytokines upon extracellular (TLR) and intracellular (inflammasome) pathogen recognition.

The early inflammatory response to tissue damage includes vasodilation of blood vessels upstream of an infection while capillary permeability to the affected tissue is increased, resulting in extravasation (leaving the capillaries into tissue) of plasma proteins. This exudate contains non-specific neutrophils which can destroy the infective causative agent (e.g. bacteria) and break down and liquefy the damaged tissue so that the debris can be removed from the site of damage. If inflammation of the affected site persists, cytokines like IL-1b and TNF-a will be released which activate endothelial cells to up regulate receptors (VCAM-1, ICAM-1, E-selectin, and L-selectin) for various immune cells to induce an antigen-specific and regulated immune response. Receptor up-regulation increases extravasation of neutrophils, monocytes, activated T-helper and T-cytotoxic, and memory T and B cells to the infected site. In addition to local effects in inflammation, there is a systemic reaction known as the acute-phase response (APR), best characterized by pronounced changes in the concentration of certain circulating proteins (e.g. C reactive protein (CRP)) and multiple alterations in lipid (e.g. prostaglandins) and lipoprotein metabolism. APR-induced alterations initially protect the host from the harmful effects of bacteria, viruses and parasites. However, if prolonged these changes in the structure and function of lipoproteins will contribute to atherogenesis. Moreover, chronic or persistent inflammation can facilitate the formation of cancer development.

Inflammation Triggers & Innate Immunity

In a broad sense, immunity can be classified into an innate and an adaptive or acquired immune response. Each response is important in host defense against invading pathogens such as bacteria and viruses. The highly specific adaptive immune system requires days to weeks to refine Igs and cell-mediated immune recognition systems to eliminate invading pathogens. The innate immune system is often the first line of defense against pathogens. A conserved set of receptors called pattern-recognition receptors has evolved to recognize molecular patterns commonly associated with many microbial agents. These patterns are referred to as pathogen-associated molecular patterns (PAMPs). Thus, cells (e.g. macrophages and dendritic cells (CD)) of the innate immune system, by recognizing these PAMPs, are able to distinguish self from nonself molecular structures and initiate the host defense consisting of the activation of signalling events that induce the expression of effector molecules, such as cytokines and costimulatory molecules. These effector molecules may subsequently induce an adaptive immune response.

Receptors recognizing these PAMPs are referred to as pathogen-recognition receptors (PRRs). The best known of these are the Toll-like receptors (TLRs), but a number of other receptors are also involved including acute phase response proteins of the pentraxin family, C-type lectins (e.g. DC-SIGN), scavenger receptors, peptidoglycan recognition proteins (PGRPs) and most recently NACHT-LRRs (NLRs), which are suggested to detect intracellular pathogens or danger signals in general.

Toll-like Receptors

The initial recognition of microbes during host defense is mediated by a family of receptors termed Toll-like-receptors (TLR) [1]. Activation of the TLRs leads not only to the induction of inflammatory responses, but also to the development of antigen-specific innate and adaptive immunity [2, 3]. TLRs recognize conserved microbial components, termed pathogen-associated molecular patterns (PAMPs). To date, 10 TLRs have been cloned in human and each receptor appears to be involved in the recognition of a unique set of PAMPs that are distinct in their chemical nature and structure [4]. TLRs can be divided into two categories with regard to the subcellular localisation. Cell surface TLRs includes TLR1/TLR2, TLR4 /MD2, TLR5 and TLR6 /TLR2 whereas TLR3, TLR7, TLR8 and TLR9 are found in intracellular organelles[5]. Toll-like receptors are characterized by an extracellular domain composed of leucine-rich repeats (LRRs), and an intracytoplasmic domain with a conserved region found in TLRs as well as in Interleukin-1 receptor (Toll/IL-1R or TIR domain). TLR intracellular domains specifically recruit several adaptor proteins including MyD88, TIRAP/MAL, TRIF, and TOLLIP[6]. These adaptor proteins subsequently associate with a family of Interleukin-1 Receptor-Associated Kinases (IRAK1, 2, M, and 4). Recruitments of numerous downstream signaling proteins lead to activation of a range of transcription factors such as NF-kappaB, AP-1, and IRFs, which are responsible for specific gene transcription [7].

TLR ligands

Biochemical studies and genetic analyses using transgenic mice have revealed specific ligands for the activation of the TLR receptors. Of the 10 human TLRs described to date, only TLR10 is an orphan receptor. TLR1, TLR2 and TLR6 (both as homo- and heterodimers) detect lipopeptide [4], while TLR3, TLR7, TLR8 and TLR9 recognize nucleic acids [5]. TLR5 senses Flagellin, a protein found in the flagella of gram-negative bacteria [8] and TLR4 recognizes a diverse collection of lipopolysaccharides (LPS) [9]. The extracellular region including the LRRs either directly or indirectly binds to their respective ligands. For instance, MD2, CD14 anf LPS-binding protein (LBP) are the co-receptors of TLR4, while flagellin and unmethylated CpG oligonucleotides directly interact with TLR5 ad TLR9, respectively [9].

LITERATURE OVERVIEW:

1. Akira, S., and Takeda, K. (2004). Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499-511.

2. Iwasaki, A., and Medzhitov, R. (2004). Toll-like receptor control of the adaptive immune responses. Nat. Immunol. 5, 987-995.

3. Cook, D.N., Pisetsky, D.S., and Schwartz, D.A. (2004). Toll-like receptors in the pathogenesis of human disease. Nat. Immunol. 5, 975-979.

4. Miyake, K. (2007). Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Sem. Immunol. 19, 3-10.

5. Krieg, A.M., and Vollmer, J. (2007). Toll-like receptors 7, 8, and 9: linking innate immunity to autoimmunity. Immunol. Rev. 220, 251-269.

6. Watters, T.M., Kenny, E.F., and O'Neill, L.A. (2007). Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunol. Cell Biol. 85, 411-419.

7. Lee, M.S., and Kim, Y.J. (2007). Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu. Rev. Biochem. 76, 447-480.

8. Smith, K.D., and Ozinsky, A. (2002). Toll-like receptor-5 and the innate immune response to bacterial flagellin. Curr. Top. Microbiol. Immunol. 270, 93-108.

9. Miller, S.I., Ernst, R.K., and Bader, M.W. (2005). LPS, TLR4 and infectious disease diversity. Nat Rev Microbiol 3, 36-46.