RT info:eu-repo/semantics/doctoralThesis
T1 Regulación de la activación del inflasoma NLRP3 por LIPINA-2 en macrófagos
A1 Lordén Losada, Gema
A2 Universidad de Valladolid. Instituto de Biología y Genética Molecular (IBGM)
K1 Inmunidad innata
K1 2412 Inmunología
K1 2302 Bioquímica
AB The innate immune system constitutes the first line of defense against invading microbial pathogens, as it can discriminate self from non-self. It can also sense endogenous danger signals that are released from disrupted host tissue or stressed cells. Macrophages, cells of the innate immune system, are able to recognize PAMPs and DAMPs by different receptors that modulate inflammation through transcriptional (TLRs) and post-transcriptional (NLRs) mechanisms. Key players in those pathways are large intracellular multiprotein complexes called inflammasomes. After exposure to pathogens and danger signals, inflammasomes orchestrate innate immune responses through activation of caspase-1 leading to the maturation of pro-inflammatory cytokines pro-IL-1β and pro-IL-18 and an inflammatory form of death known as pyroptosis. NLRP3 inflammasome is the best characterized to date. It is composed of an NLR receptor, the adaptor protein ASC and pro-caspase-1. In macrophages, its activation and assembly need two signals. The first signal, also known as priming, leads to transcription of genes encoding pro-IL-1β and NLRP3 and it is mediated by activation of the transcription factor NF-κB through various receptors, such as TLRs, IL1R or TNFR. The second signal, provided by DAMPs, activates the inflammasome assembly, resulting in the catalytic processing of pro-caspase-1 into its enzymatically active form. NLRP3 inflammasome is activated by a wide range of stimuli, such as bacterial and viral pathogens, pore-forming toxins, lipids, crystals, vaccine adjuvants and stress cellular signals such as ATP. It is broadly agreed that detection of such a diverse variety of agents cannot bind to NLRP3 directly. Instead, it is thought that NLRP3 monitors a common host-derived factor triggered by all these agents. Several hypotheses on molecular mechanisms leading to NLRP3 activation have been formulated. Three models that may not be exclusive are the most widely accepted. The first model suggests that a decrease in intracellular potassium concentration causes inflammasome activation, the second model points at mitochondrial damage and ROS production, and the third model claims that lysosomal destabilization is the mechanism triggering caspase-1 activation.
YR 2016
FD 2016
LK http://uvadoc.uva.es/handle/10324/39212
UL http://uvadoc.uva.es/handle/10324/39212
LA spa
NO Departamento de Bioquímica y Biología Molecular y Fisiología
DS UVaDOC
RD 22-nov-2024