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.
Highlights
In multiple sclerosis (MS) and in the animal model experimental autoimmune encephalomyelitis (EAE), the acute disease state is associated with T cell extravasation into the central nervous system (CNS), elevated levels of macrophage/monocyte derived cytokines such as interleukin(IL)-1b, and macrophage mediated myelin phagocytosis, whereas the chronic disease phase is associated with ongoing cellular losses [1,2].ATP is involved in diverse signaling platforms and is well known for inducing excitotoxic cell death within the nervous system
In multiple sclerosis (MS) and in the animal model experimental autoimmune encephalomyelitis (EAE), the acute disease state is associated with T cell extravasation into the CNS, elevated levels of macrophage/monocyte derived cytokines such as interleukin(IL)-1b, and macrophage mediated myelin phagocytosis, whereas the chronic disease phase is associated with ongoing cellular losses [1,2]
To what was recorded in rats, daily injections of MFQ (5.0 mg/kg; starting 7 dpi) in mice immunized with MOG delayed onset and reduced EAE symptoms compared to MFQ-untreated EAE mice (Fig. 1C; P,0.05; N = 19–20 mice)
Summary
ATP is involved in diverse signaling platforms and is well known for inducing excitotoxic cell death within the nervous system. ATP initiates an excitotoxic cascade that culminates in apoptosis of oligodendrocytes. Pharmacologic inhibition of the ATP-sensitive ionotropic P2X7 receptor (P2X7R) reduces demyelination, axonal damage, and oligodendrocyte cell death in white matter ischemia and in EAE [3,4]. The non-lytic mechanism of ATP release in EAE has yet to be defined. Under whole-cell patch clamp recordings, P2X7R activation by ATP is marked by an initial small conductance followed by a protracted larger conductance permissive to molecules up to
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