Martín Sánchez, María Rosario Fátima

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Martín Sánchez, María Rosario Fátima

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Farmacología

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Open Access
Expression and extinction of morphine-related aversive memories in mice: underlying neural substrates and impact of morphine encapsulation in liposomes
(IntechOpen, 2025-10-08) Martínez Laorden, Elena; Martín Sánchez, María Rosario Fátima; Fernández López, Lucía; Cánovas Cabanes, Alberto; Teruel Fernández, Francisco Javier; Navarro Zaragoza, Javier; Almela Rojo, Pilar; Farmacología
The conditioned-place aversion (CPA) paradigm is a widely used animal model for determining the dysphoric and aversive properties of withdrawal, as well as to study the neural substrates underlying the aversive memory associated with drug withdrawal. Therefore, one of the aims of the present chapter was to investigate possible strain differences in morphine-withdrawn mice after CPA training. Different studies have shown that corticotrophin-releasing factor (CRF) is critically involved in aversion-driven associative learning. So, we also measured the effects of CP-154,526, a selective CRF1 receptor (CRF1R) antagonist, on CPA activation and extinction and on brain-derived neurotrophic factor (BDNF) expression in dentate gyrus (DG) and basolateral amygdala (BLA), two limbic areas that play a critical role in emotional learning and memory. In the last section of the chapter, we show our main results concerning the effects of encapsulating morphine in liposomes on CPA expression and extinction. Our results indicate a crucial role for CRF, through CRF1R, in molecular changes involved in aversive memory expression and extinction demonstrating that CRF1R antagonists might be a potential therapeutic target in drug addiction. Finally, morphine encapsulation in liposomes could mitigate the progress of addiction and constitute a good option for the therapeutic use of this drug.
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Morphine withdrawal regulates phosphorylation of cAMP response element binding protein (CREB) through PKC in the nucleus tractus solitarius-A2 catecholaminergic neurons
(Wiley, 2009-08-10) Martín Sánchez, María Rosario Fátima; Laorden Carrasco, María Luisa; Milanés Maquilón, María Victoria; Farmacología
The transcription factor cAMP response element binding protein (CREB) has been implicated in the actions of drugs of abuse in several brain areas. However, little is known about CREB regulation in the nucleus tractus solitarius (NTS)-A2 catecholaminergic cell group, one of the key regions of the brain stress system. Morphine withdrawal modulates gene expression in the NTS through various second- messenger signal transduction systems including activation of extracellular signal-regulated kinases 1/2 (ERK1/2) and protein kinase C (PKC). In the current study we used immunoblotting and immunohistochemistry to investigate changes in CREB phosphorylation in the NTS and kinases that may mediate the morphine withdrawal-triggered activation of CREB and hypothalamo- pituitary-adrenocortical (HPA) axis (another stress system circuit) response after naloxone-induced morphine withdrawal. We found an increased phosphorylation of REB (pCREB) selectively within tyrosine hydroxylase (TH) immunoreactive neurons in the NTS from morphine- withdrawn rats, which parallel elevated corticosterone levels. We also measured expression levels of TH and phosphorylated ERK1/2 (pERK1/2), and found that both are up-regulated following morphine withdrawal. SL327, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK1/2 levels, did not attenuated the rise in pCREB and TH immunoreactivity or plasma corticosterone secretion during morphine withdrawal, indicating that ERK kinase/ERK pathway was not directly needed for either activation of CREB and TH expression in the NTS or HPA axis hyperactivity. In contrast, PKC inhibitor calphostin C reduced the withdrawal-triggered rise in pCREB, pERK1/2, TH expression and corticosterone secretion. The results indicate that PKC mediates both CREB activation and HPA response by morphine withdrawal and might suggest that CREB activation in the NTS is related to TH expression associated with morphine withdrawal.
Open Access
The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response
(Nature, 2014) Baroja-Mazo, Alberto; Gomez, Ana I.; Amores-Iniesta, Joaquín; Compan, Vincent; Barberá-Cremades, María; Yagüe, Jordi; Ruiz-Ortiz, Estibaliz; Antón, Jordi; Buján, Segundo; Couillin, Isabelle; Brough, David; Arostegui, Juan I.; Martínez Cáceres, Carlos Manuel; Martín Sánchez, María Rosario Fátima; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
NLRP3 inflammasome assembly activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β, and thereby plays a central role in the inflammatory response and in diverse human diseases. Here we report that upon caspase-1 activation oligomerized NLRP3-inflammasome particles are released from macrophages. Recombinant oligomeric protein particles composed of the adapter protein ASC or the cryopyrin-associated periodic syndromes (CAPS) mutant NLRP3 p.D303N, stimulate further caspase-1 activation extracellularly, and also intracellularly upon phagocytosis by surrounding macrophages. ASC oligomeric particles were found in the serum of patients with active CAPS, but not in patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3-inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.
Open Access
Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins
(Nature Research, 2016-07-01) Martín Sánchez, María Rosario Fátima; Tyrkalska, Sylwia D.; Candel Camacho, Sergio; Angosto, Diego; Gómez Abellán, Victoria; García Moreno, Diana; Zapata Pérez, Rubén; Sánchez Ferrer, Álvaro; Pelegrín Vivancos, Pablo; Mulero Méndez, Victoriano Francisco; Sepulcre Cortés, María Pilar; Farmacología
Inflammasomes are cytosolic molecular platforms that alert the immune system about thepresence of infection. Here we report that zebrafish guanylate-binding protein 4 (Gbp4),an IFNg-inducible GTPase protein harbouring a C-terminal CARD domain, is required for theinflammasome-dependent clearance of Salmonella Typhimurium (ST) by neutrophils in vivo.Despite the presence of the CARD domain, Gbp4 requires the universal inflammasomeadaptor Asc for mediating its antibacterial function. In addition, the GTPase activity of Gbp4is indispensable for inflammasome activation and ST clearance. Mechanistically, neutrophilsare recruited to the infection site through the inflammasome-independent production of thechemokine (CXC motif) ligand 8 and leukotriene B4, and then mediate bacterial clearancethrough the Gbp4 inflammasome-dependent biosynthesis of prostaglandin D2. Our resultspoint to GBPs as key inflammasome adaptors required for prostaglandin biosynthesis andbacterial clearance by neutrophils and suggest that transient activation of the inflammasomemay be used to treat bacterial infections.
Open Access
Early endosome autoantigen 1 regulates IL-1β release upon caspase-1 activation independently of gasdermin D membrane permeabilization
(Nature Research, 2019-04-08) Martín Sánchez, María Rosario Fátima; Baroja Mazo, Alberto; Compan, Vince; Tapia Abellán, Ana; Coullin, Isabelle; Pelegrín Vivancos, Pablo; Farmacología
Unconventional protein secretion represents an important process of the inflammatory response.The release of the pro-inflammatory cytokine interleukin (IL)-1β which burst during pyroptosis asa consequence of gasdermin D plasma membrane pore formation, can also occur through otherunconventional secretion pathways dependent on caspase-1 activation. However, how caspase-1mediates cytokine release independently of gasdermin D remains poorly understood. Here weshow that following caspase-1 activation by different inflammasomes, caspase-1 cleaves earlyendosome autoantigen 1 (EEA1) protein at Asp127/132 . Caspase-1 activation also results in the releaseof the endosomal EEA1 protein in a gasdermin D-independent manner. EEA1 knock-down resultsin adecreased release of caspase-1 and IL-1β, but the pyroptotic release of other inflammasomecomponents and lactate dehydrogenase was not affected. This study shows how caspase-1 control therelease of EEA1 and IL-1β in a pyroptotic-independent manner
Open Access
Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages
(2021-09-28) Diaz del Olmo, Ines; Worboys, Jonathan; Martín Sánchez, María Rosario Fátima; Gritsenko, Anna; Ambrose, Ashley R.; Tannahill, Gillian M.; Nichols, Eva-Maria; Lopez-Castejon, Gloria; Davis, Daniel M.; Famacología
Interleukin 1b (IL-1b) plays a major role in inflammation and is secreted by immune cells,such as macrophages, upon recognition of danger signals. Its secretion is regulated bythe inflammasome, the assembly of which results in caspase 1 activation leading togasdermin D (GSDMD) pore formation and IL-1b release. During inflammation, dangersignals also activate the complement cascade, resulting in the formation of the membraneattack complex (MAC). Here, we report that stimulation of LPS-primed humanmacrophages with sub-lytic levels of MAC results in activation of the NOD-like receptor3 (NLRP3) inflammasome and GSDMD-mediated IL-1b release. The MAC is firstinternalized into endosomes and then colocalizes with inflammasome components;adapter protein apoptosis associated speck-like protein containing a CARD (ASC) andNLRP3. Pharmacological inhibitors established that MAC-triggered activation of theNLRP3 inflammasome was dependent on MAC endocytosis. Internalization of the MACalso caused dispersion of the trans-Golgi network. Thus, these data uncover a role for theMAC in activating the inflammasome and triggering IL-1b release in human macrophages.
Open Access
Inflammasome-dependent IL-1β release depends upon membrane permeabilisation
(Nature, 2016) Diamon, Catherine; Zeitler, Marcel; Gomez-Sanchez, Ana; Baroja-Mazo, Alberto; Bagnall, James; Spiller, David; White, Michael; Daniels, Michael J. D.; Mortellaro, Alessandra; Peñalver, Marcos; Paszek, Pawel; Steringer, Julia P.; Nickel, Walter; Brough, David; Martín Sánchez, María Rosario Fátima; Pelegrín Vivancos, Pablo; Bioquímica y Biología Molecular B e Inmunología
Interleukin (IL)-1β is a critical regulator of the inflammatory response. IL-1β is not secreted through the conventional ER-Golgi route of protein secretion and to-date its mechanism of release has been unknown. Crucially its secretion depends upon the processing of a precursor form following the activation of the multi-molecular inflammasome complex. Using a novel and reversible pharmacological inhibitor of the IL-1β release process, in combination with biochemical, biophysical and real-time single-cell confocal microscopy with macrophage cells expressing Venus labelled IL-1β, we have discovered that the secretion of IL-1β after inflammasome activation requires membrane permeabilisation, and occurs in parallel with the death of the secreting cell. Thus in macrophages the release of IL-1β in response to inflammasome activation appears to be a secretory process independent of non-specific leakage of proteins during cell death. The mechanism of membrane permeabilisation leading to IL-1β release is distinct from the unconventional secretory mechanism employed by its structural homologues FGF2 or IL-1α, a process that involves the formation of membrane pores but does not result in cell death. These discoveries reveal key processes at the initiation of an inflammatory response and deliver new insights into mechanisms of protein release.
Open Access
Priming is dispensable for NLRP3 inflammasome activation in human monocytes in vitro
(Frontiers Media, 2020-09-30) Martín Sánchez, María Rosario Fátima; Gritsenko, Anna; Yu, Shi; Díaz del Olmo, Inés; Nichols, Eva María; Davis, Daniel M.; Brough, David; López Castejón, Gloria; Farmacología
Interleukin (IL)-18 and IL-1b are potent pro-inflammatory cytokines that contribute toinflammatory conditions such as rheumatoid arthritis and Alzheimer’s disease. They areproduced as inactive precursors that are activated by large macromolecular complexescalled inflammasomes upon sensing damage or pathogenic signals. NLRP3inflammasome activation is regarded to require a priming step that causes NLRP3 andIL-1b gene upregulation, and also NLRP3 post-translational licencing. A subsequentactivation step leads to the assembly of the complex and the cleavage of pro-IL-18 andpro-IL-1b by caspase-1 into their mature forms, allowing their release. Here we show thathuman monocytes, but not monocyte derived macrophages, are able to form canonicalNLRP3 inflammasomes in the absence of priming. NLRP3 activator nigericin caused theprocessing and release of constitutively expressed IL-18 in an unprimed setting. This wasmediated by the canonical NLRP3 inflammasome that was dependent on K + and Cl−efflux and led to ASC oligomerization, caspase-1 and Gasdermin-D (GSDMD) cleavage.IL-18 release was impaired by the NLRP3 inhibitor MCC950 and by the absence ofNLRP3, but also by deficiency of GSDMD, suggesting that pyroptosis is the mechanism ofrelease. This work highlights the readiness of the NLRP3 inflammasome to assemble inthe absence of priming in human monocytes and hence contribute to the very early stagesof the inflammatory response when IL-1b has not yet been produced. It is important toconsider the unprimed setting when researching the mechanisms of NLRP3 activation, asto not overshadow the pathways that occur in the absence of priming stimuli, which mightonly enhance this response.
Open Access
The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response
(Nature Research, 2014-08) Baroja Mazo, Alberto; Gómez, Ana I.; Amores Iniesta, Joaquín; Compan, Vincent; Barberà Cremades, María; Yagüe, Jordi; Ruiz Ortiz, Estibaliz; Antón, Jordi; Buján, Segundo; Coullin, Isabelle; Brough, David; Arostegui, Juan I.; Martínez Cáceres, Carlos Manuel; Martín Sánchez, María Rosario Fátima; Pelegrín Vivancos, Pablo; Anatomía y Anatomía Patológica Comparadas
Assembly of the NLRP3 inflammasome activates caspase-1 and mediates the processing and release of the leaderless cytokine IL-1β and thereby serves a central role in the inflammatory response and in diverse human diseases. Here we found that upon activation of caspase-1, oligomeric NLRP3 inflammasome particles were released from macrophages. Recombinant oligomeric protein particles composed of the adaptor ASC or the p.D303N mutant form of NLRP3 associated with cryopyrin-associated periodic syndromes (CAPS) stimulated further activation of caspase-1 extracellularly, as well as intracellularly after phagocytosis by surrounding macrophages. We found oligomeric ASC particles in the serum of patients with active CAPS but not in that of patients with other inherited autoinflammatory diseases. Our findings support a model whereby the NLRP3 inflammasome, acting as an extracellular oligomeric complex, amplifies the inflammatory response.
Open Access
Macrophage activation and polarization modify P2X7 receptor secretome influencing the inflammatory process
(Nature Research, 2016-03-03) Carlos de Torre-Minguela; Maria Barberà-Cremades; Ana I. Gómez; Martín Sánchez, María Rosario Fátima; Pelegrín Vivancos, Pablo; Farmacología
The activation of P2X7 receptor (P2X7R) on M1 polarized macrophages induces the assembly of the NLRP3 inflammasome leading to the release of pro-inflammatory cytokines and the establishment of the inflammatory response. However, P2X7R signaling to the NLRP3 inflammasome is uncoupled on M2 macrophages without changes on receptor activation. In this study, we analyzed P2X7R secretome in wild-type and P2X7R-deficient macrophages polarized either to M1 or M2 and proved that proteins released after P2X7R stimulation goes beyond caspase-1 secretome. The characterization of P2X7R-secretome reveals a new function of this receptor through a fine-tuning of protein release. We found that P2X7R stimulation in macrophages is able to release potent anti-inflammatory proteins, such as Annexin A1, independently of their polarization state suggesting for first time a potential role for P2X7R during resolution of the inflammation and not linked to the release of pro-inflammatory cytokines. These results are of prime importance for the development of therapeutics targeting P2X7R.