Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis
Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demo...
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| description | Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility. |
| doi_str_mv | 10.1371/journal.pone.0076907 |
| format | Article |
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Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0076907</identifier><identifier>PMID: 24130809</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animal models ; Animals ; Autoantigens ; Autoimmune diseases ; Autoimmunity ; Cannabinoid CB1 receptors ; Cannabinoid CB2 receptors ; Cannabis ; Capsaicin receptors ; Clonal deletion ; Dentistry ; Disease Models, Animal ; Disease susceptibility ; Encephalomyelitis ; Encephalomyelitis, Autoimmune, Experimental - genetics ; Encephalomyelitis, Autoimmune, Experimental - immunology ; Endocannabinoid system ; Experimental allergic encephalomyelitis ; Female ; Gene Deletion ; Gene Knockout Techniques ; Genes ; Glycoproteins ; House mouse ; Immune response ; Immune system ; Immunomodulation ; Immunomodulation - genetics ; Immunosuppression ; Influence ; Laboratory animals ; Ligands ; Lymphocytes T ; Male ; Marijuana ; Medical marijuana ; Medicine ; Mice ; Multiple sclerosis ; Multiple Sclerosis - genetics ; Multiple Sclerosis - immunology ; Myelin ; Myelin proteins ; Nervous system ; Oligodendrocyte-myelin glycoprotein ; Pharmacology ; Phenotype ; Proteins ; Receptor, Cannabinoid, CB2 - deficiency ; Receptor, Cannabinoid, CB2 - genetics ; Receptors ; Receptors, Cannabinoid - deficiency ; Receptors, Cannabinoid - genetics ; Rodents ; Species Specificity ; Spinal cord ; T cells ; Tetrahydrocannabinol ; Transient receptor potential proteins</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e76907</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Sisay et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Sisay et al 2013 Sisay et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c659t-3d667b33e02d13714a43f6eb51042fa0506477120f55c1f5052d2f0d848798243</citedby><cites>FETCH-LOGICAL-c659t-3d667b33e02d13714a43f6eb51042fa0506477120f55c1f5052d2f0d848798243</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793915/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793915/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24130809$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sisay, Sofia</creatorcontrib><creatorcontrib>Pryce, Gareth</creatorcontrib><creatorcontrib>Jackson, Samuel J</creatorcontrib><creatorcontrib>Tanner, Carolyn</creatorcontrib><creatorcontrib>Ross, Ruth A</creatorcontrib><creatorcontrib>Michael, Gregory J</creatorcontrib><creatorcontrib>Selwood, David L</creatorcontrib><creatorcontrib>Giovannoni, Gavin</creatorcontrib><creatorcontrib>Baker, David</creatorcontrib><title>Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.</description><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Autoantigens</subject><subject>Autoimmune diseases</subject><subject>Autoimmunity</subject><subject>Cannabinoid CB1 receptors</subject><subject>Cannabinoid CB2 receptors</subject><subject>Cannabis</subject><subject>Capsaicin receptors</subject><subject>Clonal deletion</subject><subject>Dentistry</subject><subject>Disease Models, Animal</subject><subject>Disease susceptibility</subject><subject>Encephalomyelitis</subject><subject>Encephalomyelitis, Autoimmune, Experimental - genetics</subject><subject>Encephalomyelitis, Autoimmune, Experimental - immunology</subject><subject>Endocannabinoid system</subject><subject>Experimental allergic encephalomyelitis</subject><subject>Female</subject><subject>Gene Deletion</subject><subject>Gene Knockout Techniques</subject><subject>Genes</subject><subject>Glycoproteins</subject><subject>House mouse</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunomodulation</subject><subject>Immunomodulation - genetics</subject><subject>Immunosuppression</subject><subject>Influence</subject><subject>Laboratory animals</subject><subject>Ligands</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Marijuana</subject><subject>Medical marijuana</subject><subject>Medicine</subject><subject>Mice</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis - genetics</subject><subject>Multiple Sclerosis - immunology</subject><subject>Myelin</subject><subject>Myelin proteins</subject><subject>Nervous system</subject><subject>Oligodendrocyte-myelin glycoprotein</subject><subject>Pharmacology</subject><subject>Phenotype</subject><subject>Proteins</subject><subject>Receptor, Cannabinoid, CB2 - deficiency</subject><subject>Receptor, Cannabinoid, CB2 - genetics</subject><subject>Receptors</subject><subject>Receptors, Cannabinoid - deficiency</subject><subject>Receptors, Cannabinoid - genetics</subject><subject>Rodents</subject><subject>Species Specificity</subject><subject>Spinal cord</subject><subject>T cells</subject><subject>Tetrahydrocannabinol</subject><subject>Transient receptor potential 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Gavin</au><au>Baker, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-10-09</date><risdate>2013</risdate><volume>8</volume><issue>10</issue><spage>e76907</spage><pages>e76907-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Endocannabinoids and some phytocannabinoids bind to CB1 and CB2 cannabinoid receptors, transient receptor potential vanilloid one (TRPV1) receptor and the orphan G protein receptor fifty-five (GPR55). Studies using C57BL/10 and C57BL/6 (Cnr2 (tm1Zim)) CB2 cannabinoid receptor knockout mice have demonstrated an immune-augmenting effect in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis. However, other EAE studies in Biozzi ABH mice often failed to show any treatment effect of either CB2 receptor agonism or antagonism on inhibition of T cell autoimmunity. The influence of genetic background on the induction of EAE in endocannabinoid system-related gene knockout mice was examined. It was found that C57BL/6.GPR55 knockout mice developed less severe disease, notably in female mice, following active induction with myelin oligodendrocyte glycoprotein 35-55 peptide. In contrast C57BL/6.CB2 (Cnr2 (Dgen)) receptor knockout mice developed augmented severity of disease consistent with the genetically and pharmacologically-distinct, Cnr2 (tm1Zim) mice. However, when the knockout gene was bred into the ABH mouse background and EAE induced with spinal cord autoantigens the immune-enhancing effect of CB2 receptor deletion was lost. Likewise CB1 receptor and transient receptor potential vanilloid one knockout mice on the ABH background demonstrated no alteration in immune-susceptibility, in terms of disease incidence and severity of EAE, in contrast to that reported in some C57BL/6 mouse studies. Furthermore the immune-modulating influence of GPR55 was marginal on the ABH mouse background. Whilst sedative doses of tetrahydrocannabinol could induce immunosuppression, this was associated with a CB1 receptor rather than a CB2 receptor-mediated effect. These data support the fact that non-psychoactive doses of medicinal cannabis have a marginal influence on the immune response in MS. Importantly, it adds a note of caution for the translational value of some transgenic/gene knockout and other studies on low-EAE susceptibility backgrounds with inconsistent disease course and susceptibility.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24130809</pmid><doi>10.1371/journal.pone.0076907</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-10, Vol.8 (10), p.e76907 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1440829396 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Analysis Animal models Animals Autoantigens Autoimmune diseases Autoimmunity Cannabinoid CB1 receptors Cannabinoid CB2 receptors Cannabis Capsaicin receptors Clonal deletion Dentistry Disease Models, Animal Disease susceptibility Encephalomyelitis Encephalomyelitis, Autoimmune, Experimental - genetics Encephalomyelitis, Autoimmune, Experimental - immunology Endocannabinoid system Experimental allergic encephalomyelitis Female Gene Deletion Gene Knockout Techniques Genes Glycoproteins House mouse Immune response Immune system Immunomodulation Immunomodulation - genetics Immunosuppression Influence Laboratory animals Ligands Lymphocytes T Male Marijuana Medical marijuana Medicine Mice Multiple sclerosis Multiple Sclerosis - genetics Multiple Sclerosis - immunology Myelin Myelin proteins Nervous system Oligodendrocyte-myelin glycoprotein Pharmacology Phenotype Proteins Receptor, Cannabinoid, CB2 - deficiency Receptor, Cannabinoid, CB2 - genetics Receptors Receptors, Cannabinoid - deficiency Receptors, Cannabinoid - genetics Rodents Species Specificity Spinal cord T cells Tetrahydrocannabinol Transient receptor potential proteins |
| title | Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T01%3A52%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genetic%20background%20can%20result%20in%20a%20marked%20or%20minimal%20effect%20of%20gene%20knockout%20(GPR55%20and%20CB2%20receptor)%20in%20experimental%20autoimmune%20encephalomyelitis%20models%20of%20multiple%20sclerosis&rft.jtitle=PloS%20one&rft.au=Sisay,%20Sofia&rft.date=2013-10-09&rft.volume=8&rft.issue=10&rft.spage=e76907&rft.pages=e76907-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0076907&rft_dat=%3Cgale_plos_%3EA478353536%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1440829396&rft_id=info:pmid/24130809&rft_galeid=A478353536&rft_doaj_id=oai_doaj_org_article_0d32f5bcecba45b6acecca178110bd73&rfr_iscdi=true |