Astrocyte CB(1) receptors drive blood-brain barrier disruption in central nervous system 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 CB(1) receptors (CB(1)R) expressed by neurons and oligodendrocyte lineage cells, endocannabinoid signaling restricts neurodegeneration and promotes remyelination in preclinical MS models. However, despite accumulating evidence that supports cell-specific roles for CB(1)R in brain physiology and pathology, the implications of astrocyte CB(1)R signaling in MS initiation and progression remain uncertain. Using complementary in vivo disease models, here we investigated the effects of targeted genetic deletion of astrocyte CB(1)R on the expression of MS-like pathology in mice. Interestingly, astrocyte-specific deletion of CB(1)R reduced demyelinating neuropathology, attenuated astrocyte reactivity and improved clinical deficits during the time-course of experimental autoimmune encephalomyelitis (EAE). Mice with astrocyte CB(1)R inactivation displayed unaltered oligodendrocyte populations both in EAE plaques and in lysolecithin-induced remyelinating spinal cord lesions, likely excluding that CB(1)R expressed by astroglial cells modulate myelin repair processes. Conversely, inactivation of CB(1)R in astrocytes 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 astrocyte CB(1)R null mice. These results show that astrocyte CB(1)R signaling constitutes a significant pro-inflammatory mechanism in experimental 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-026-03708-3.