Inhibitory role for GABA in autoimmune inflammation

Bhat, R.; Axtell, Robert C.; Mitra, Ananya; Miranda, Melissa; Lock, Christopher; Tsien, Richard W.; Steinman, Lawrence

doi:10.1073/pnas.0915139107

Cited by 415 publications

(416 citation statements)

References 44 publications

(42 reference statements)

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“…Chronically enhanced levels of inflammatory cytokines impairs neuronal function, leading in turn to a further decrease in the efficacy of neuronal control over glial activity and thus to an accelerated age-dependent progression of glial activation. This is consistent with previous studies showing that GABAergic interneurons in the hippocampus are important regulators of microglial activity (53) and with the proposed role of the endocannabinoid system in neuroprotection (54). Our results suggest that enhanced neuroinflammation together with the degeneration of pyramidal cells lead to an early onset of cognitive deficits in the absence of CB1 signaling on GABAergic neurons.…”

Section: Discussionsupporting

confidence: 82%

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

Albayram

Alferink

Pitsch

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits. Mice lacking the Cnr1 gene (Cnr1 −/− ), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated agedependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1 −/− mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1 −/− mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells. Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.glial regulation | Morris water maze | stereological quantification | CD40 expression | telemetric EEG recording

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Section: Discussionsupporting

confidence: 82%

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

Albayram

Alferink

Pitsch

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The GABA pathway was shown to have inhibitory effects on the immune system, and GABA agonists could suppress CNS inflammation in vivo (44). In stroke, GABA modulation beginning 3 d after stroke promoted functional recovery but did not influence the size of the stroke (43), in contrast to the current results with Cryab, where stroke size was reduced when the treatment was started even 12 h after the stroke.…”

Section: Discussioncontrasting

confidence: 56%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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128

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Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of αB-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab −/− mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

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“…Traditionally, it has been thought that the functions of immune cells such as T cells and DCs are regulated mainly by cytokines. However, a number of more recent studies have shown that immune system cells can also be regulated by neurotransmitters (6)(7)(8)(9)(10)(11). Consistent with this, both primary and secondary lymphoid organs are highly innervated by sympathetic ends that store dopamine (DA) (12,13).…”

Section: Endritic Cells (Dcs) Are the Most Efficient Type Of Apcsmentioning

confidence: 73%

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

Prado

Contreras

González

et al. 2012

The Journal of Immunology

114

132

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Dendritic cells (DCs) are responsible for priming T cells and for promoting their differentiation from naive T cells into appropriate effector cells. Emerging evidence suggests that neurotransmitters can modulate T cell-mediated immunity. However, the involvement of specific neurotransmitters or receptors remains poorly understood. In this study, we analyzed the role of dopamine in the regulation of DC function. We found that DCs express dopamine receptors as well as the machinery necessary to synthesize, store, and degrade dopamine. Notably, the expression of D5R decreased upon LPS-induced DC maturation. Deficiency of D5R on the surface of DCs impaired LPS-induced IL-23 and IL-12 production and consequently attenuated the activation and proliferation of Ag-specific CD4+ T cells. To determine the relevance of D5R expressed on DCs in vivo, we studied the role of this receptor in the modulation of a CD4+ T cell-driven autoimmunity model. Importantly, D5R-deficient DCs prophylactically transferred into wild-type recipients were able to reduce the severity of experimental autoimmune encephalomyelitis. Furthermore, mice transferred with D5R-deficient DCs displayed a significant reduction in the percentage of Th17 cells infiltrating the CNS without differences in the percentage of Th1 cells compared with animals transferred with wild-type DCs. Our findings demonstrate that by contributing to CD4+ T cell activation and differentiation to Th17 phenotype, D5R expressed on DCs is able to modulate the development of an autoimmune response in vivo.

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Inhibitory role for GABA in autoimmune inflammation

Cited by 415 publications

References 44 publications

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

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