{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T10:07:47Z","timestamp":1785146867583,"version":"3.55.0"},"reference-count":108,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>The endocannabinoid system (ECS) is increasingly recognized as a central regulator of immune homeostasis, integrating neural, metabolic, and immune signaling to maintain physiological equilibrium. This Perspective examines the \u201ctherapeutic paradox\u201d of endocannabinoid immunomodulation, whereby anti-inflammatory and tissue-protective effects are mechanistically linked to transient immunosuppression. Although cannabinoid receptor 2 (CB2) is the primary mediator of immune regulation, growing evidence indicates that cannabinoid receptor 1 (CB1) also contributes to inflammatory control in both the central nervous system and peripheral tissues. Activation of CB2 suppresses inflammatory signaling through Gi\/o-mediated inhibition of adenylate cyclase, reduced cyclic adenosine monophosphate (cAMP) signaling, and repression of nuclear factor kappa B (NF-\u03baB)-dependent transcription. While these mechanisms limit pathological inflammation and promote tissue protection, they simultaneously attenuate innate and adaptive immune functions required for effective pathogen clearance. Across neuroinflammatory disorders, inflammatory bowel disease, hepatic injury, sepsis, cancer, and systemic inflammatory syndromes, the ECS shifts immune responses toward resolution at the cost of reduced antimicrobial readiness. We synthesize the molecular mechanisms underlying this therapeutic paradox, including macrophage polarization, lymphocyte reprogramming, and tissue-specific immune adaptations, and discuss strategies for developing endocannabinoid-based therapeutics that preserve anti-inflammatory efficacy while minimizing immunosuppressive liabilities.<\/jats:p>","DOI":"10.3390\/ijms27156626","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Therapeutic Paradox of Endocannabinoid Immunomodulation: Molecular Mechanisms and Strategic Frameworks"],"prefix":"10.3390","volume":"27","author":[{"given":"Cameron R.","family":"Love","sequence":"first","affiliation":[{"name":"Center for Advanced Biotechnology and Medicine, Rutgers University, 679 Hoes Lane, Piscataway, NJ 08854, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and physiological roles of inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.cell.2015.02.010","article-title":"Homeostasis, inflammation, and disease susceptibility","volume":"160","author":"Kotas","year":"2015","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1038\/nature01320","article-title":"Points of control in inflammation","volume":"420","author":"Nathan","year":"2002","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature13479","article-title":"Pro-resolving lipid mediators are leads for resolution physiology","volume":"510","author":"Serhan","year":"2014","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1038\/nature06005","article-title":"Unravelling the pathogenesis of inflammatory bowel disease","volume":"448","author":"Xavier","year":"2007","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.cell.2010.02.016","article-title":"Mechanisms underlying inflammation in neurodegeneration","volume":"140","author":"Glass","year":"2010","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/nri2402","article-title":"Harmful molecular mechanisms in sepsis","volume":"8","author":"Rittirsch","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Almogi-Hazan, O., and Or, R. (2020). Cannabis, the endocannabinoid system and immunity. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124448"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nrd1495","article-title":"The endocannabinoid system and its therapeutic exploitation","volume":"3","author":"Bifulco","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1124\/pr.58.3.2","article-title":"The endocannabinoid system as an emerging target of pharmacotherapy","volume":"58","author":"Pacher","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1038\/nrn1247","article-title":"The molecular logic of endocannabinoid signalling","volume":"4","author":"Piomelli","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1152\/physrev.00019.2008","article-title":"Endocannabinoid-mediated control of synaptic transmission","volume":"89","author":"Kano","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1126\/science.1470919","article-title":"Isolation and structure of a brain constituent that binds to the cannabinoid receptor","volume":"258","author":"Devane","year":"1992","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1006\/bbrc.1995.2437","article-title":"2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain","volume":"215","author":"Sugiura","year":"1995","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/346561a0","article-title":"Structure of a cannabinoid receptor and functional expression of the cloned cDNA","volume":"346","author":"Matsuda","year":"1990","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1038\/365061a0","article-title":"Molecular characterization of a peripheral receptor for cannabinoids","volume":"365","author":"Munro","year":"1993","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1111\/j.1432-1033.1995.tb20780.x","article-title":"Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations","volume":"232","author":"Mary","year":"1995","journal-title":"Eur. J. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1017\/S1462399409000957","article-title":"Emerging role of the cannabinoid receptor CB2 in immune regulation","volume":"11","author":"Cabral","year":"2009","journal-title":"Expert Rev. Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s12026-011-8210-5","article-title":"Unraveling the complexities of cannabinoid receptor 2 (CB2) immune regulation","volume":"51","author":"Basu","year":"2011","journal-title":"Immunol. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/nri1602","article-title":"Cannabinoid-based drugs as anti-inflammatory therapeutics","volume":"5","author":"Klein","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.4155\/fmc.09.93","article-title":"Cannabinoids as novel anti-inflammatory drugs","volume":"1","author":"Nagarkatti","year":"2009","journal-title":"Future Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ol\u00e1h, A., Szekanecz, Z., and B\u00edr\u00f3, T. (2017). Targeting cannabinoid signaling in the immune system: \u201cHigh\u201d-ly exciting questions, possibilities, and challenges. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01487"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.phrs.2009.03.019","article-title":"Endocannabinoids and immune regulation","volume":"60","author":"Pandey","year":"2009","journal-title":"Pharmacol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"\u0218erban, M., Tero-Vescan, A., Bungau, S., and Behl, T. (2025). The endocannabinoid system in human disease and immune regulation. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262211132"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Thai, B., Tsuji, K., and Marshall, J.C. (2025). The endocannabinoid system in sepsis: A scoping review. Biomedicines, 13.","DOI":"10.3390\/anesthres2040024"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1007\/s00018-016-2300-4","article-title":"The CB2 receptor and its role as a regulator of inflammation","volume":"73","author":"Turcotte","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_28","first-page":"20","article-title":"Endocannabinoid signaling at the nanomolecular level","volume":"36","author":"Maccarrone","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1038\/sj.ijo.0803272","article-title":"The pharmacology of cannabinoid receptors and their ligands: An overview","volume":"30","author":"Pertwee","year":"2006","journal-title":"Int. J. Obes."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/imm.12441","article-title":"Endocannabinoid signalling in innate and adaptive immunity","volume":"144","author":"Battistini","year":"2015","journal-title":"Immunology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1016\/j.chembiol.2007.11.006","article-title":"A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol","volume":"14","author":"Blankman","year":"2007","journal-title":"Chem. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1083\/jcb.200305129","article-title":"Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain","volume":"163","author":"Bisogno","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/384083a0","article-title":"Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides","volume":"384","author":"Cravatt","year":"1996","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"10819","DOI":"10.1073\/pnas.152334899","article-title":"Brain monoglyceride lipase participating in endocannabinoid inactivation","volume":"99","author":"Dinh","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1687","DOI":"10.1021\/cr0782067","article-title":"Enzymatic pathways that regulate endocannabinoid signaling in the nervous system","volume":"108","author":"Ahn","year":"2008","journal-title":"Chem. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/nrd2553","article-title":"Targeting the endocannabinoid system: To enhance or reduce?","volume":"7","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.drudis.2010.03.007","article-title":"Endocannabinoid biosynthesis and inactivation, from simple to complex","volume":"15","author":"Muccioli","year":"2010","journal-title":"Drug Discov. Today"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.neuropharm.2008.07.037","article-title":"Endocannabinoid signaling in microglial cells","volume":"56","author":"Stella","year":"2009","journal-title":"Neuropharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/imm.13378","article-title":"Endocannabinoids in immune regulation and immunopathologies","volume":"164","author":"Rahaman","year":"2021","journal-title":"Immunology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3135","DOI":"10.2174\/138161206777947425","article-title":"Cannabinoids, Immune System and Cytokine Network","volume":"12","author":"Massi","year":"2006","journal-title":"Curr. Pharm. Des."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jneuroim.2005.04.023","article-title":"Cannabinoids and the immune system: Potential for the treatment of inflammatory diseases?","volume":"166","author":"Croxford","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_42","first-page":"214","article-title":"CB2 cannabinoid receptor agonist JWH-015 triggers apoptosis in macrophage-like cells","volume":"81","author":"Lombard","year":"2007","journal-title":"J. Leukoc. Biol."},{"key":"ref_43","first-page":"104218","article-title":"Endocannabinoids and immunological dynamics","volume":"357","author":"Ray","year":"2020","journal-title":"Cell. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1172\/JCI200419465","article-title":"The endogenous cannabinoid system protects against colonic inflammation","volume":"113","author":"Massa","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1111\/febs.12260","article-title":"Modulating the endocannabinoid system in human health and disease\u2014successes and failures","volume":"280","author":"Pacher","year":"2013","journal-title":"FEBS J."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Hryhorowicz, S., Kaczmarek-Ry\u015b, M., Zieli\u0144ska, A., Scott, R.J., S\u0142omski, R., and P\u0142awski, A. (2021). Endocannabinoid System as a Promising Therapeutic Target in Inflammatory Bowel Disease\u2014A Systematic Review. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.790803"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1208\/s12248-009-9084-5","article-title":"Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation","volume":"11","author":"Burstein","year":"2009","journal-title":"AAPS J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"59","DOI":"10.3390\/dna5040059","article-title":"The CB2 Receptor in Immune Regulation and Disease: Genetic Architecture, Epigenetic Control, and Emerging Therapeutic Strategies","volume":"5","author":"Kalkan","year":"2025","journal-title":"DNA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"239","DOI":"10.2174\/1874467212666190215112036","article-title":"New Insights in Cannabinoid Receptor Structure and Signaling","volume":"12","author":"Ye","year":"2019","journal-title":"Curr. Mol. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.lfs.2005.05.055","article-title":"Cannabinoid signalling","volume":"78","author":"Demuth","year":"2006","journal-title":"Life Sci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Rakotoarivelo, V., Mayer, T.Z., Simard, M., Flamand, N., and Di Marzo, V. (2024). The Impact of the CB2 Cannabinoid Receptor in Inflammatory Diseases: An Update. Molecules, 29.","DOI":"10.3390\/molecules29143381"},{"key":"ref_52","first-page":"14841","article-title":"Regulatory Role of the Cannabinoid Type 2 Receptor in Inflammation and Autoimmunity","volume":"24","author":"Ribeiro","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"ref_53","unstructured":"Ma, L., Shen, F.G., Wu, M.R., Wang, W., Xia, B.W., and Ma, Y.S. (2021). The Cannabinoid Receptor 2 Agonist JWH-133 Inhibits Lipopolysaccharide-Induced Inflammation in Macrophages via the NF-\u03baB and MAPK Signaling Pathways. Front. Pharmacol., 12."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.cell.2008.01.020","article-title":"Shared principles in NF-kappaB signaling","volume":"132","author":"Hayden","year":"2008","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3376","DOI":"10.1073\/pnas.92.8.3376","article-title":"Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide","volume":"92","author":"Facci","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","first-page":"1","article-title":"The cannabinoid system and cytokine network","volume":"225","author":"Klein","year":"2000","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_57","first-page":"227","article-title":"The anti-inflammatory activities of cannabinoid receptor ligands in mouse peritonitis models","volume":"399","author":"Smith","year":"2000","journal-title":"Eur. J. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Podini\u0107, T., Werstuck, G., and Raha, S. (2023). The implications of cannabinoid-induced metabolic dysregulation for cellular differentiation and growth. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241311003"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Haspula, D., and Clark, M.A. (2020). Cannabinoid receptors: An update on cell signaling, pathophysiological roles and therapeutic opportunities in neurological, cardiovascular, and inflammatory diseases. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21207693"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nn.3053","article-title":"Mitochondrial CB1 receptors regulate neuronal energy metabolism","volume":"15","author":"Massa","year":"2012","journal-title":"Nat. Neurosci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3342","DOI":"10.1098\/rstb.2011.0393","article-title":"Endocannabinoids in neuroendopsychology: Multiphasic control of mitochondrial function","volume":"367","author":"Nunn","year":"2012","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1152\/ajpendo.00100.2014","article-title":"Mitochondria: A possible nexus for the regulation of energy homeostasis by the endocannabinoid system?","volume":"307","author":"Lipina","year":"2014","journal-title":"Am. J. Physiol.-Endocrinol. Metab."},{"key":"ref_63","first-page":"114","article-title":"Identification and functional characterization of mitochondrial cannabinoid receptor 2 (mtCB2) in regulating immune cell metabolic reprogramming and bioenergetic shifts","volume":"20","author":"Tu","year":"2023","journal-title":"J. Neuroinflamm."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1523\/JNEUROSCI.4212-08.2009","article-title":"Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels","volume":"29","author":"Ryan","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Liu, Q.R., Aseer, K.R., Yao, Q., Zhong, X., Ghosh, P., O\u2019Connell, J.F., and Egan, J.M. (2022). Anti-inflammatory and pro-autophagy effects of the cannabinoid receptor CB2R: Possibility of modulation in type 1 diabetes. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.809965"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.phrs.2012.11.002","article-title":"Cannabinoid agonists increase the interaction between \u03b2-Arrestin 2 and ERK1\/2 and upregulate \u03b2-Arrestin 2 and 5-HT2A receptors","volume":"68","author":"Franklin","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Zheng, C., Chen, L., Chen, X., He, X., Yang, J., Shi, Y., and Zhou, N. (2013). The Second Intracellular Loop of the Human Cannabinoid CB2 Receptor Governs G Protein Coupling in Coordination with the Carboxyl Terminal Domain. PLoS ONE, 8.","DOI":"10.1371\/annotation\/11146424-f236-4fc6-85b2-cd393cfb6a94"},{"key":"ref_68","first-page":"173304","article-title":"CB2 receptor agonist JWH-133 attenuates chronic inflammation by reprogramming macrophage polarization through the Nrf2\/HO-1 pathway","volume":"882","author":"Wu","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/j.freeradbiomed.2009.07.035","article-title":"Nrf2:INrf2 (Keap1) signaling in oxidative stress","volume":"47","author":"Kaspar","year":"2009","journal-title":"Free Radic. Biol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/s41573-018-0008-x","article-title":"Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases","volume":"18","author":"Cuadrado","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/s41577-020-00491-x","article-title":"Regulation of inflammation by the antioxidant haem oxygenase 1","volume":"21","author":"Campbell","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_72","first-page":"112","article-title":"The dual roles of natural cannabidiol in combating oxidative stress and inflammation: A potential intestinal guardian","volume":"212","author":"Lv","year":"2026","journal-title":"Free Radic. Biol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"5831315","DOI":"10.1155\/2016\/5831315","article-title":"Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation","volume":"2016","author":"McCoy","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.it.2004.09.015","article-title":"The chemokine system in diverse forms of macrophage activation and polarization","volume":"25","author":"Mantovani","year":"2004","journal-title":"Trends Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: Nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/nri2448","article-title":"Exploring the full spectrum of macrophage activation","volume":"8","author":"Mosser","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.immuni.2010.05.007","article-title":"Alternative activation of macrophages: Mechanism and functions","volume":"32","author":"Gordon","year":"2010","journal-title":"Immunity"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3733","DOI":"10.4049\/jimmunol.181.6.3733","article-title":"Macrophage polarization in bacterial infections","volume":"181","author":"Benoit","year":"2008","journal-title":"J. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: In vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"13","DOI":"10.12703\/P6-13","article-title":"The M1 and M2 paradigm of macrophage activation: Time for reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_81","unstructured":"Rossi, F., Tortora, C., Argenziano, M., Di Paola, A., Punzo, F., Carotenuto, M., Ametrano, O., Maresca, R., Signoriello, G., and Miraglia del Giudice, E. (2025). Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Inflammatory Bowel Disease. Int. J. Mol. Sci., 26."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Argenziano, M., Pota, V., Di Paola, A., Tortora, C., Di Pinto, D., Pagnini, F., Di Martino, M., and Rossi, F. (2023). CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043345"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Younis, N.S. (2022). \u03b2-Caryophyllene Ameliorates Cyclophosphamide Induced Cardiac Injury: The Association of TLR4\/NF\u03baB and Nrf2\/HO1\/NQO1 Pathways. J. Cardiovasc. Dev. Dis., 9.","DOI":"10.3390\/jcdd9050133"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"3358","DOI":"10.1002\/eji.201040667","article-title":"Cannabinoid receptor activation leads to massive mobilization of myeloid-derived suppressor cells","volume":"40","author":"Hegde","year":"2010","journal-title":"Eur. J. Immunol."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Yekhtin, Z., Moshrefi, M., Chen, Y., Zuo, P., and Kunos, G. (2022). Differential effects of THC and CBD treatments on macrophage immune function in vitro. Biomedicines, 10.","DOI":"10.3390\/biomedicines10081793"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1124\/jpet.114.220368","article-title":"Protective role of cannabinoid receptor 2 activation in galactosamine\/lipopolysaccharide-induced acute liver failure through regulation of macrophage polarization and microRNAs","volume":"353","author":"Tomar","year":"2015","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_87","first-page":"1416","article-title":"CB2R agonist GW405833 alleviates acute liver failure in mice via inhibiting HIF-1\u03b1-mediated reprogramming of glycometabolism and macrophage proliferation","volume":"44","author":"Wang","year":"2023","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Ke, P., Shao, B.Z., Xu, Z.Q., Wei, W., Han, B.Z., Chen, X.W., Liu, C., and Shi, D.F. (2016). Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155076"},{"key":"ref_89","first-page":"139","article-title":"Cannabinoids Receptor-2 (CB2) agonist ameliorates colitis in IL-10\u2212\/\u2212 mice by attenuating the activation of T cells and promoting their apoptosis","volume":"294","author":"Singh","year":"2012","journal-title":"Toxicology"},{"key":"ref_90","first-page":"417","article-title":"Cannabinoid Receptor 2 Functional Variant Contributes to the Risk for Pediatric Inflammatory Bowel Disease","volume":"51","author":"Strisciuglio","year":"2017","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Shake, E.P., Santos, G.V., and Sivaraman, V. (2026). Alcohol and cannabinoids differentially regulate macrophage polarization, with co-exposure producing an antagonistic immunomodulatory effect. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27094054"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/S0165-5728(02)00370-3","article-title":"\u03949-Tetrahydrocannabinol regulates Th1\/Th2 cytokine balance in activated human T cells","volume":"133","author":"Yuan","year":"2002","journal-title":"J. Neuroimmunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/S0162-3109(98)00041-1","article-title":"Delta9 tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells","volume":"40","author":"Srivastava","year":"1998","journal-title":"Immunopharmacology"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.imbio.2009.04.001","article-title":"Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression","volume":"215","author":"Rieder","year":"2010","journal-title":"Immunobiology"},{"key":"ref_95","first-page":"41530","article-title":"MicroRNA-690 regulates immunosuppressive mechanisms in Tregs after cannabinoid exposure","volume":"286","author":"Hegde","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"373","DOI":"10.4049\/jimmunol.165.1.373","article-title":"Delta-9-tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway","volume":"165","author":"Zhu","year":"2000","journal-title":"J. Immunol."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Franks, L.N. (2025). Editorial: The role of cannabinoids and the endocannabinoid system in anti-cancer therapy. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2026.1754350"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"3605","DOI":"10.1182\/blood.V92.10.3605","article-title":"Modulation and functional involvement of CB2 peripheral cannabinoid receptors during B-cell differentiation","volume":"92","author":"Carayon","year":"1998","journal-title":"Blood"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s11481-015-9603-3","article-title":"Effects of cannabinoids on T-cell function and resistance to infection","volume":"10","author":"Eisenstein","year":"2015","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/S0026-895X(25)09237-5","article-title":"Activation of NF-kappaB by lipopolysaccharide is inhibited by cannabinoids","volume":"50","author":"Jeon","year":"1996","journal-title":"Mol. Pharmacol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"118044","DOI":"10.1016\/j.biopha.2025.118044","article-title":"Cannabinoid receptor 2 (CB2R) as potential target for the pharmacological treatment of neurodegenerative diseases","volume":"186","author":"Meanti","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1053\/j.gastro.2016.04.015","article-title":"The Role of the Endocannabinoid System in the Brain\u2013Gut Axis","volume":"151","author":"Sharkey","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"964518","DOI":"10.1155\/2015\/964518","article-title":"Mechanisms of Neuronal Protection against Excitotoxicity, Endoplasmic Reticulum Stress, and Mitochondrial Dysfunction in Stroke and Neurodegenerative Diseases","volume":"2015","author":"Prentice","year":"2015","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Nagappan, A., Shin, J., and Jung, M.H. (2019). Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092109"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Bazwinsky-Wutschke, I., Zipprich, A., and Dehghani, F. (2019). Endocannabinoid System in Hepatic Glucose Metabolism, Fatty Liver Disease, and Cirrhosis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20102516"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"211","DOI":"10.5114\/ceh.2024.145358","article-title":"Cannabinoids and the endocannabinoid system in liver diseases","volume":"10","author":"Martonik","year":"2024","journal-title":"Clin. Exp. Hepatol."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Miranda, K., Mehrpouya-Bahrami, P., Nagarkatti, P.S., and Nagarkatti, M. (2019). Cannabinoid Receptor 1 Blockade Attenuates Obesity and Adipose Tissue Type 1 Inflammation Through miR-30e-5p Regulation of Delta-Like-4 in Macrophages and Consequently Downregulation of Th1 Cells. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.01049"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Caruso, E.A., De Nunzio, V., Tutino, V., and Notarnicola, M. (2025). The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26031306"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6626\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:50:00Z","timestamp":1785145800000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6626"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,25]]},"references-count":108,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156626"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156626","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,25]]}}}