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López, Alicia

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Alicia

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López

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    Role of interleukin 1-beta in the inflammatory response in a fatty acid amide hydrolase-knockout mouse model of Alzheimer’s disease.
    (Biochemical Pharmacology, 2018) Aparicio, Noelia; Grande Rodríguez, Mª Teresa; Ruiz de Martín Esteban, Samuel; López, Alicia; Ruiz Pérez, Gonzalo; Amores, Mario; Vázquez, Carmen; Martínez Relimpio, Ana María; Ruth Pazos, M.; Cravatt, Benjamin F.; Tolón, Rosa María; Romero, Julián
    The search for novel therapies for the treatment of Alzheimer’s disease is an urgent need, due to the current paucity of available pharmacological tools and the recent failures obtained in clinical trials. Among other strategies, the modulation of amyloid-triggered neuroinflammation by the endocannabinoid system seems of relevance. Previous data indicate that the enhancement of the endocannabinoid tone through the inhibition of the enzymes responsible for the degradation of their main endogenous ligands may render beneficial effects. Based on previously reported data, in which we described a paradoxical effect of the genetic deletion of the fatty acid amide hydrolase, we here aimed to expand our knowledge on the role of the endocannabinoid system in the context of Alzheimer’s disease. To that end, we inhibited the production of interleukin-1, one of the main inflammatory cytokines involved in the neuroinflammation triggered by amyloid peptides, in a transgenic mouse model of this disease by using minocycline, a drug known to impair the synthesis of this cytokine. Our data suggest that interleukin-1 may be instrumental in order to achieve the beneficial effects derived of fatty acid amide hydrolase genetic inactivation. This could be appreciated at the molecular (cytokine expression, amyloid production, plaque deposition) as well as behavioral levels (memory impairment). We here describe a previously unknown link between the endocannabinoid system and interleukin-1 in the context of Alzheimer’s disease that open new possibilities for the development of novel therapeutics.
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    Signaling through the type 2 cannabinoid receptor regulates the severity of acute and chronic graft-versus-host disease.
    (Blood, 2021) Yuan, Cheng-Yin; Zhou, Vivian; Sauber, Garrett; Stollenwerk, Todd; Komorowski, Richard; López, Alicia; Tolón, Rosa María; Romero, Julián; Hillard, Cecilia J.; Drobyski, William R.
    Graft versus host disease (GVHD) pathophysiology is a complex interplay between cells that comprise the adaptive and innate arms of the immune system. Effective prophylactic strategies are therefore contingent upon approaches that address contributions from both immune cell compartments. In the current study, we examined the role of the type 2 cannabinoid receptor (CB2R) which is expressed on nearly all immune cells and demonstrated that absence of the CB2R on donor CD4+ or CD8+ T cells, or administration of a selective CB2R pharmacological antagonist, exacerbated acute GVHD lethality. This was accompanied primarily by the expansion of proinflammatory CD8+ T cells indicating that constitutive CB2R expression on T cells preferentially regulated CD8+ T cell alloreactivity. Using a novel CB2REGFP reporter mouse, we observed significant loss of CB2R expression on T cells, but not macrophages, during acute GVHD, indicative of differential alterations in receptor expression under inflammatory conditions. Therapeutic targeting of the CB2R with the agonists, tetrahydrocannabinol (THC) and JWH- 133, revealed that only THC mitigated lethal T cell-mediated acute GVHD. Conversely, only JWH-133 was effective in a sclerodermatous chronic GVHD model where macrophages contribute to disease biology. In vitro, both THC and JWH-133 induced arrestin recruitment and ERK phosphorylation via CB2R, but THC had no effect on CB2R-mediated inhibition of adenylyl cyclase. These studies demonstrate that the CB2R plays a critical role in the regulation of GVHD and suggest that effective therapeutic targeting is dependent upon agonist signaling characteristics and receptor selectivity in conjunction with the composition of pathogenic immune effector cells.
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    Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease.
    (Journal of Neuroinflammation, 2018) López, Alicia; Aparicio, Noelia; Pazos, M. Ruth; Grande Rodríguez, Mª Teresa; Barreda Manso, Mª Asunción; Benito Cuesta, Irene; Vázquez, Carmen; Amores, Mario; Ruiz Pérez, Gonzalo; García García, Elena; Beatka, Margaret; Tolón, Rosa María; Dittel, Bonnie N.; Hillard, Cecilia J.; Romero, Julián
    Background: Because of their low levels of expression and the inadequacy of current research tools, CB2 cannabinoid receptors (CB2R) have been difficult to study, particularly in the brain. This receptor is especially relevant in the context of neuroinflammation, so novel tools are needed to unveil its pathophysiological role(s). Methods: We have generated a transgenic mouse model in which the expression of enhanced green fluorescent protein (EGFP) is under the control of the cnr2 gene promoter through the insertion of an Internal Ribosomal Entry Site followed by the EGFP coding region immediately 3′ of the cnr2 gene and crossed these mice with mice expressing five familial Alzheimer’s disease (AD) mutations (5xFAD). Results: Expression of EGFP in control mice was below the level of detection in all regions of the central nervous system (CNS) that we examined. CB2R-dependent-EGFP expression was detected in the CNS of 3-month-old AD mice in areas of intense inflammation and amyloid deposition; expression was coincident with the appearance of plaques in the cortex, hippocampus, brain stem, and thalamus. The expression of EGFP increased as a function of plaque formation and subsequent microgliosis and was restricted to microglial cells located in close proximity to neuritic plaques. AD mice with CB2R deletion exhibited decreased neuritic plaques with no changes in IL1β expression. Conclusions: Using a novel reporter mouse line, we found no evidence for CB2R expression in the healthy CNS but clear up-regulation in the context of amyloid-triggered neuroinflammation. Data from CB2R null mice indicate that they play a complex role in the response to plaque formation.