Astrocyte CB₁receptors drive blood-brain barrier disruption in CNS inflammatory disease

Reactive astrocytes shape central nervous system (CNS) inflammation and participate in myelin damage and repair mechanisms in multiple sclerosis (MS). Through the activation of cannabinoid CB₁receptors (CB₁R) expressed by neurons and oligodendrocyte lineage cells, endocannabinoid signaling restricts neurodegeneration and promote remyelination in preclinical MS models. However, despite accumulating evidence that supports a crucial role for these receptor populations in brain physiology and pathology, the implications of astrocyte CB₁R signaling in MS initiation and progression remain uncertain. Using complementaryin vivodisease models, here we investigated the effects of targeted genetic deletion of astrocytes CB₁R on the expression of MS-like pathology in mice. Interestingly, astrocyte-specific deletion of CB₁R reduced demyelinating neuropathology, attenuated astrocyte reactivity and improved clinical deficits during the time-course of experimental autoimmune encephalomyelitis (EAE). Mice with astrocyte CB₁R inactivation displayed unaltered oligodendrocyte populations both in EAE lesions and in lysolecithin-induced remyelinating spinal cord lesions, likely excluding that astrocyte CB₁R modulate myelin repair processes. Conversely, inactivation of CB₁R in astroglial cells restricted humoral and leukocyte parenchymal infiltration and reduced the expression of vascular effectors in EAE lesions. Finally, loss of blood-brain barrier (BBB) function induced by cortical microinjection of VEGF-A was less severe in GFAP-CB₁R-KO mice. These results show that astrocyte CB₁R signaling constitutes a significant pro-inflammatory mechanism in MS and bring to light a deleterious role for endocannabinoid-mediated modulation of astroglial cells with potential implications in the etiopathology and therapy of neuroinflammatory disorders.