Astrocyte CB1 receptors drive blood-brain barrier disruption in central nervous system inflammatory disease

Colomer T(#)(1)(2)(3), Bernal-Chico A(#)(1)(2)(3), Sánchez-Martín E(#)(1)(2)(3),
Moreno-García A(1)(2)(3), Baraibar AM(1)(2)(3), Uribe-Irusta A(1)(2),
Iriarte-Sarria A(1)(2), Beriain S(4), Skupio U(4), Gatuingt-Chasseriaud C(4),
Gonzales D(4), Laplagne G(4), Serrat R(4), de Guevara IP(5)(6)(7), Matute
C(1)(3)(7), Clemente D(5)(6)(7), Tepavcevic V(2)(7)(8)(9), Fernández-Moncada
I(4)(10), Chapouly C(11), Marsicano G(4), Mato S(12)(13)(14).

Author information:
(1)Department of Neurosciences, University of the Basque Country UPV/EHU, Leioa,
48940, Spain.
(2)Achucarro Basque Center for Neuroscience, Leioa, 48940, Spain.
(3)Neuroimmunology Group, Biobizkaia Health Research Institute, Barakaldo,
48903, Spain.
(4)University of Bordeaux, INSERM, Neurocentre Magendie, U1215, Bordeaux, 33000,
France.
(5)Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos (SESCAM), Toledo,
45071, Spain.
(6)Castile-La Mancha Health Research Institute (IDISCAM), Toledo, 45071, Spain.
(7)Centro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED), Madrid, 28029, Spain.
(8)Laboratory of Comparative and Regenerative Neurobiology, Cavanilles Institute
of Biodiversity and Evolutionary Biology, University of Valencia, Paterna,
46980, Spain.
(9)Department of Cell Biology, Functional Biology and Physical Anthropology,
University of Valencia, Burjassot, 46100, Spain.
(10)University of Bordeaux, INRAE, Bordeaux INP, NutriNeurO, UMR 1286, Bordeaux,
33000, France.
(11)University of Bordeaux, INSERM, BMC, U1034, Pessac, 33600, France.
(12)Department of Neurosciences, University of the Basque Country UPV/EHU,
Leioa, 48940, Spain. .
(13)Achucarro Basque Center for Neuroscience, Leioa, 48940, Spain.
.
(14)Neuroimmunology Group, Biobizkaia Health Research Institute, Barakaldo,
48903, Spain. .
(#)Contributed equally

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 CB1 receptors (CB1R) 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 CB1R in
brain physiology and pathology, the implications of astrocyte CB1R 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 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 plaques and in lysolecithin-induced remyelinating spinal cord lesions,
likely excluding that CB1R expressed by astroglial cells modulate myelin repair
processes. Conversely, inactivation of CB1R 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 CB1R
null mice. These results show that astrocyte CB1R 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.

DOI: 10.1186/s12974-026-03708-3
PMCID: PMC12924220
PMID: 41606632

Conflict of interest statement: Declarations. Competing interests: The authors
declare no competing interests.

Auteurs Bordeaux Neurocampus