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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.

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 Toll-like receptor (TLR) multigene family encodes important recognition receptors of the innate immune system that have been conserved in both the invertebrate and vertebrate lineages [1]. TLRs recognize conserved molecular products derived from various classes of pathogens, including Gram-positive and -negative bacteria, DNA and RNA viruses, fungi and protozoa. TLR genes have been recognized in a number of vertebrate genomes, and many partial and full-length sequences are available. Eleven TLRs have been identified in humans while 13 can be found in searches of the mouse genome. Human and mouse TLR family members have been shown to have distinct ligand specifities, recognizing different molecular structures. TLR11, which in mice responds to uropathogenic bacteria [2] and a profilin-like protein from Toxoplasma gondii [3], in humans is non-functional because of the presence of a stop codon in the gene (pseudogene) [2]. TLR1, TLR2, TLR4, TLR5 and TLR6 are all localized to the plasma membrane recognizing cell wall components, while TLR3, TLR7, TLR8 and TLR9 are preferentially expressed in intracellular compartments such as endosomes and recognize nucleic acid structures. RP105 (CD180) [4] is a TLR homolog lacking a signalling domain inhibiting the ability of TLR4 to bind its microbial ligand in vitro and in vivo [5].

LITERATURE OVERVIEW:

[1] The evolution of vertebrate Toll-like receptors: J.C. Roach, et al.; PNAS 102, 9577 (2005)

[2] A toll-like receptor that prevents infection by uropathogenic bacteria: D. Zhang, et al.; Science 303, 1522 (2004)

[3] TLR11 activation of dendritic cells by a protozoan profilin-like protein: F. Yarovinsky, et al.; Science 308, 1626 (2005)

[4] RP105, a novel B cell surface molecule implicated in B cell activation, is a member of the leucine-rich repeat protein family: K. Miyake, et al.; J. Immunol. 154, 3333 (1995)

[5] Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105: S. Divanovic, et al.; Nat. Immunol. 6, 571 (2005)