title: Contribution of pannexin1 to experimental autoimmune encephalomyelitis.
abstract: Pannexin1 (Panx1) is a plasma membrane channel permeable to relatively large molecules, such as ATP. In the central nervous system (CNS) Panx1 is found in neurons and glia and in the immune system in macrophages and T-cells. We tested the hypothesis that Panx1-mediated ATP release contributes to expression of Experimental Autoimmune Encephalomyelitis (EAE), an animal model for multiple sclerosis, using wild-type (WT) and Panx1 knockout (KO) mice. Panx1 KO mice displayed a delayed onset of clinical signs of EAE and decreased mortality compared to WT mice, but developed as severe symptoms as the surviving WT mice. Spinal cord inflammatory lesions were also reduced in Panx1 KO EAE mice during acute disease. Additionally, pharmacologic inhibition of Panx1 channels with mefloquine (MFQ) reduced severity of acute and chronic EAE when administered before or after onset of clinical signs. ATP release and YoPro uptake were significantly increased in WT mice with EAE as compared to WT non-EAE and reduced in tissues of EAE Panx1 KO mice. Interestingly, we found that the P2X7 receptor was upregulated in the chronic phase of EAE in both WT and Panx1 KO spinal cords. Such increase in receptor expression is likely to counterbalance the decrease in ATP release recorded from Panx1 KO mice and thus contribute to the development of EAE symptoms in these mice. The present study shows that a Panx1 dependent mechanism (ATP release and/or inflammasome activation) contributes to disease progression, and that inhibition of Panx1 using pharmacology or gene disruption delays and attenuates clinical signs of EAE.
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lutz
authors.forename: Estibaliz
authors.initials: E
authors.lastname: González-Fernández
authors.forename: Juan Carlos Chara
authors.initials: JC
authors.lastname: Ventura
authors.forename: Alberto
authors.initials: A
authors.lastname: Pérez-Samartín
authors.forename: Leonid
authors.initials: L
authors.lastname: Tarassishin
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Negoro
authors.forename: Naman K
authors.initials: NK
authors.lastname: Patel
authors.forename: Sylvia O
authors.initials: SO
authors.lastname: Suadicani
authors.forename: Sunhee C
authors.initials: SC
authors.lastname: Lee
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
authors.forename: Eliana
authors.initials: E
authors.lastname: Scemes
mesh_terms: D000818:Animals; D001483:Base Sequence; D017630:Connexins / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology
chemical_list: D017630:Connexins; D017931:DNA Primers; D053583:Interleukin-1beta; D009419:Nerve Tissue Proteins; C503631:Panx1 protein, mouse; D058486:Receptors, Purinergic P2X7