title: Molecular mechanisms of regulation of Toll-like receptor signaling.
abstract: TLRs play a critical role in the detection of microbes and endogenous "alarmins" to initiate host defense, yet they can also contribute to the development and progression of inflammatory and autoimmune diseases. To avoid pathogenic inflammation, TLR signaling is subject to multilayer regulatory control mechanisms, including cooperation with coreceptors, post-translational modifications, cleavage, cellular trafficking, and interactions with negative regulators. Nucleic acid-sensing TLRs are particularly interesting in this regard, as they can both recognize host-derived structures and require internalization of their ligand as a result of intracellular sequestration of the nucleic acid-sensing TLRs. This review summarizes the regulatory mechanisms of TLRs, including regulation of their access to ligands, receptor folding, intracellular trafficking, and post-translational modifications, as well as how altered control mechanism could contribute to inflammatory and autoimmune disorders.
authors.affiliation: Department of Microbiology and Immunology, Cornell University, Ithaca, New York, USA; and cal59@cornell.edu.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Leifer
authors.affiliation: Department of Immunology, University of Connecticut Heath Center, Farmington, Connecticut, USA.
authors.forename: Andrei E
authors.initials: AE
authors.lastname: Medvedev
mesh_terms: D056704:Adaptive Immunity; D000067531:Alarmins / Q000276:immunology; D000818:Animals; D019281:Dimerization; D011992:Endosomes / Q000276:immunology; D006031:Glycosylation; D006801:Humans; D007113:Immunity, Innate; D007239:Infections / Q000276:immunology; D008024:Ligands; D009696:Nucleic Acids / Q000276:immunology; D010766:Phosphorylation; D011485:Protein Binding; D000072417:Protein Domains; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction / Q000276:immunology*; D013329:Structure-Activity Relationship; D051193:Toll-Like Receptors / Q000276:immunology* / Q000648:ultrastructure; D054875:Ubiquitination
chemical_list: D000067531:Alarmins; D008024:Ligands; D009696:Nucleic Acids; D051193:Toll-Like Receptors
keywords: inflammation; innate immunity; macrophages; pattern recognition receptors; signal transduction