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Cannabinoid WIN55,212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation

dc.contributor.authorPérez Diego, Mario
dc.contributor.authorAngelina Querencias, Alba
dc.contributor.authorMartín De La Cruz, Leticia
dc.contributor.authorRocha-Muñoz, Andrés de la
dc.contributor.authorMaldonado, Angel
dc.contributor.authorSevilla-Ortega, Carmen
dc.contributor.authorPalomares Gracia, Óscar
dc.date.accessioned2024-01-25T10:27:25Z
dc.date.available2024-01-25T10:27:25Z
dc.date.issued2023
dc.description.abstractChronic or uncontrolled activation of myeloid cells including monocytes, macrophages and dendritic cells (DCs) is a hallmark of immune-mediated inflammatory disorders. There is an urgent need for the development of novel drugs with the capacity to impair innate immune cell overactivation under inflammatory conditions. Compelling evidence pointed out cannabinoids as potential therapeutic tools with anti-inflammatory and immunomodulatory capacity. WIN55,212-2, a non-selective synthetic cannabinoid agonist, displays protective effects in several inflammatory conditions by mechanisms partially depending on the generation of tolerogenic DCs able to induce functional regulatory T cells (Tregs). However, its immunomodulatory capacity on other myeloid cells such as monocytes and macrophages remains incompletely understood. Methods: Human monocyte-derived DCs (hmoDCs) were differentiated in the absence (conventional hmoDCs) or presence of WIN55,212-2 (WIN-hmoDCs). Cells were stimulated with LPS, cocultured with naive T lymphocytes and their cytokine production and ability to induce T cell responses were analysed by ELISA or flow cytometry. To evaluate the effect of WIN55,212-2 in macrophage polarization, human and murine macrophages were activated with LPS or LPS/IFNγ, in the presence or absence of the cannabinoid. Cytokine, costimulatory molecules and inflammasome markers were assayed. Metabolic and chromatin immunoprecipitation assays were also performed. Finally, the protective capacity of WIN55,212-2 was studied in vivo in BALB/c mice after intraperitoneal injection with LPS. Results: We show for the first time that the differentiation of hmoDCs in the presence of WIN55,212-2 generates tolerogenic WIN-hmoDCs that are less responsive to LPS stimulation and able to prime Tregs. WIN55,212-2 also impairs the pro-inflammatory polarization of human macrophages by inhibiting cytokine production, inflammasome activation and rescuing macrophages from pyroptotic cell death. Mechanistically, WIN55,212-2 induced a metabolic and epigenetic shift in macrophages by decreasing LPS-induced mTORC1 signaling, commitment to glycolysis and active histone marks in pro-inflammatory cytokine promoters. We confirmed these data in ex vivo LPS-stimulated peritoneal macrophages (PMΦs), which were also supported by the in vivo anti-inflammatory capacity of WIN55,212-2 in a LPS-induced sepsis mouse model. Conclusion: Overall, we shed light into the molecular mechanisms by which cannabinoids exert anti-inflammatory properties in myeloid cells, which might well contribute to the future rational design of novel therapeutic strategies for inflammatory disorders.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Ciencias Químicas
dc.description.refereedTRUE
dc.description.sponsorshipMinisterio de Economía y Competitividad (España)
dc.description.statuspub
dc.identifier.citationPérez-Diego M, Angelina A, Martín-Cruz L, de la Rocha-Muñoz A, Maldonado A, Sevilla-Ortega C and Palomares O (2023) Cannabinoid WIN55,212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation. Front. Immunol. 14:1147520. doi: 10.3389/fimmu.2023.1147520
dc.identifier.doi10.3389/fimmu.2023.1147520
dc.identifier.issn1664-3224
dc.identifier.officialurlhttps://doi.org/10.3389/fimmu.2023.1147520
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/37006243/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/95327
dc.journal.titleFrontiers in Immunology
dc.language.isoeng
dc.publisherFrontiers
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114396RB-I00/ES/CANNABINOIDES Y MECANISMOS MOLECULARES IMPLICADOS EN LA REGULACION DE CELULAS DENDRITICAS Y EPITELIALES HUMANAS: NUEVAS ESTRATEGIAS BASADAS EN CANNABINOIDES PARA ALERGIA/
dc.rightsAttribution 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subject.cdu577.1
dc.subject.keywordCannabinoids
dc.subject.keywordWIN55,212-2
dc.subject.keywordMonocyte differentiation
dc.subject.keywordMacrophage polarization
dc.subject.keywordImmunomodulation
dc.subject.keywordAnti-inflammatory
dc.subject.keywordMetabolic and epigenetic reprogramming
dc.subject.ucmInmunología
dc.subject.ucmBioquímica (Química)
dc.subject.ucmBiología molecular (Química)
dc.subject.unesco2412 Inmunología
dc.subject.unesco2302 Bioquímica
dc.subject.unesco2403 Bioquímica
dc.titleCannabinoid WIN55,212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number14
dspace.entity.typePublication
relation.isAuthorOfPublication09f21d21-f04a-405e-8364-59a2ab83bc61
relation.isAuthorOfPublication67a57ba8-97f2-4aa6-99d3-62cfa97da7c7
relation.isAuthorOfPublication8ed2b79b-36d7-4380-aaf1-5da770ff691d
relation.isAuthorOfPublication849d1c21-090b-4cfa-8f5b-857c7276b26d
relation.isAuthorOfPublication.latestForDiscovery09f21d21-f04a-405e-8364-59a2ab83bc61

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