A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis.

Autor:	Hashemi E; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Narain Srivastava I; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Aguirre A; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Tilahan Yoseph E; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Kaushal E; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Awani A; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Kyu Ryu J; Gladstone Institute for Neurological Disease; San Francisco, CA, USA.; Center for Neurovascular Brain Immunology at Gladstone and UCSF; San Francisco, CA USA.; Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco; San Francisco, CA, USA., Akassoglou K; Gladstone Institute for Neurological Disease; San Francisco, CA, USA.; Center for Neurovascular Brain Immunology at Gladstone and UCSF; San Francisco, CA USA.; Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco; San Francisco, CA, USA., Talebian S; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Chu P; Stanford Human Research Histology Core, Stanford University School of Medicine, Stanford, CA, USA., Pisani L; Department of Radiology, Stanford University School of Medicine Stanford, CA, USA., Musolino P; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA., Steinman L; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Doyle K; Department of Immunobiology, University of Arizona, Tucson, AZ, USA., Robinson WH; Department of Immunology & Rheumatology, Stanford University School of Medicine, Stanford, CA, USA., Sharpe O; Department of Immunology & Rheumatology, Stanford University School of Medicine, Stanford, CA, USA., Cayrol R; Department of Pathology, Clinical Department of Laboratory Medicine, University of Montreal, Quebec, Canada., Orchard P; Division of Pediatric Blood & Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA., Lund T; Division of Pediatric Blood & Marrow Transplantation, University of Minnesota, Minneapolis, MN, USA., Vogel H; Departments of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Lenail M; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Han MH; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Bonkowsky JL; Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah.; Brain and Spine Center, Primary Children's Hospital, Salt Lake City, Utah.; Primary Children's Center for Personalized Medicine, Salt Lake City, Utah., Van Haren KP; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 10. Date of Electronic Publication: 2023 Nov 10.
DOI:	10.1101/2023.11.07.564025
Abstrakt:	Objective: We sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues. Background: ALD is caused by mutations in the gene ABCD1 encoding a peroxisomal transporter. More than half of males with an ABCD1 mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in the Abcd1 -null mouse. Methods: We generated a cALD phenotype in 8-week-old, male Abcd1 -null mice by deploying a two-hit method that combines cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) models. We employed in vivo MRI and post-mortem immunohistochemistry to evaluate myelin loss, astrogliosis, blood-brain barrier (BBB) disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used bead-based immunoassay and immunohistochemistry to evaluate IL-18 in CSF and post-mortem human cALD brain tissue. Results: MRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1 -null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue. Interpretation: This novel mouse model of cALD suggests loss of Abcd1 function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination. Competing Interests: Potential Conflict of Interest K.V. serves as a scientific consultant for Poxel, bluebirdbio, and Viking Therapeutics. K.A. is the scientific founder, advisor, and shareholder of Therini Bio, Inc. Her interests are managed by Gladstone Institutes according to its conflict-of-interest policy.
Databáze:	MEDLINE
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