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Cellular Receptors for Microbes

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Cellular Receptors for Microbes

Cellular Receptors for Microbes and Damaged Cells

The receptors used by the innate immune system to react against microbes and damaged cells are expressed on phagocytes, dendritic cells, and many other cell types. These are expressed in different cellular compartments where microbes may be located. Receptors for PAMPs and DAMPs belong to several protein families.

Toll-Like Receptors

Toll-like receptors (TLRs) are homologous to a Drosophila protein called Toll. Toll was discovered for its role in the development of the fly and later shown to be essential for protecting flies against infections. TLR-2 recognizes several bacterial and parasitic glycolipids and peptidoglycans. TLR-3, -7, and -8 are specific for viral single stranded and double-stranded RNAs. TLR-4 is specific for bacterial LPS (endotoxin). TLR-5 is specific for a bacterial flagellar protein called flagellin. TLR-9 recognizes unmethylated CpG DNA, which is more abundant in microbial genomes than in mammalian DNA.

Structure and specificities of Toll-like receptors:

Different TLRs respond to many different, structurally diverse products of microbes. Endosomal TLRs respond only to nucleic acids. All TLRs contain a ligand binding domain composed of leucine-rich motifs and a cytoplasmic signaling, Toll-like interleukin-1 (IL-1) receptor (TIR) domain.
TLRs specific for microbial proteins, lipids, and polysaccharides are located on cell surfaces. TLRs that recognize nucleic acids are in endosomes, into which microbes are ingested and where the microbes are digested, and their nucleic acids are released. Signals are generated by engagement of TLRs activate transcription factors that stimulate expression of different genes. These genes encode cytokines, enzymes, and other proteins involved in the antimicrobial functions of activated phagocytes and other cells.

Signaling functions of Toll-like receptors:

TLRs activate similar signaling mechanisms, which involve adaptor proteins and lead to the activation of transcription factors. These transcription factors stimulate the production of proteins that mediate inflammation and antiviral defense.

NOD-Like Receptors and the Inflammasome
The NOD-like receptors (NLRs) are a large family of cytosolic receptors that sense DAMPs and PAMPs in the cytoplasm. Three important NLRs are NOD-1, NOD-2, and NLRP-3. NOD-1 and NOD-2 are cytosolic proteins containing N-terminal CARD (caspase related) domains. They are specific for bacterial peptidoglycans. They both activate the NF-κB transcription factor. NLRP-3 is a cytosolic NLR that responds to many unrelated microbial structures or pathologic changes in the cytosol. It reacts by enhancing production mainly of the inflammatory cytokine IL-1β. NLRP-3 recognizes microbial products that indicate cell damage and death.

NLRP-3:

After recognition of microbial substances, NLRP-3 oligomerizes with an adaptor protein. An inactive (pro) form of the enzyme caspase-1, converts to active form of this enzyme. Active caspase-1 cleaves a precursor form of the cytokine interleukin-1β (IL-1β) to generate biologically active IL-1β. IL-1 induces acute inflammation and causes fever. This cytosolic complex of NLRP-3 (the sensor), an adaptor protein, and caspase-1 is known as the inflammasome. The inflammasome is important not only for host defense but also because of its role in several diseases. Gain-of-function mutations in NLRP-3 are the cause of rare autoinflammatory syndromes. The common joint disease gout is caused by deposition of urate crystals, and subsequent inflammation mediated by inflammasome recognition of the crystals and IL-1β production.

Other Cellular Receptors of Innate Immunity:

Many other receptor types are involved in innate immune responses to microbes. The RIG-like receptor (RLR) family recognizes RNA produced by viruses in the cytosol. It activates signaling pathways that lead to the production of type I interferon (IFN).
Cytosolic DNA sensors (CDSs) include several structurally related proteins that recognize cytosolic viral DNA and induce type I IFN production.
Lectin (carbohydrate-recognizing) receptors in the plasma membrane are specific for fungal glycans (these receptors are called dectins). For terminal mannose residues (called mannose receptors); they are involved in the phagocytosis of fungi and bacteria and in inflammatory responses to these pathogens.

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