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A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis
- Source :
- Annals of Neurology, Annals of Neurology, Wiley, 2019, 85 (3), pp.406-420. ⟨10.1002/ana.25415⟩, Annals of neurology, vol. 85, no. 3, pp. 406-420, Annals of neurology, 85(3), 406-420. John Wiley and Sons Inc., Annals of Neurology, 2019, 85 (3), pp.406-420. ⟨10.1002/ana.25415⟩
- Publication Year :
- 2019
- Publisher :
- HAL CCSD, 2019.
-
Abstract
- International audience; OBJECTIVE:The two related tumor necrosis factor members a proliferation-inducing ligand (APRIL) and B-cell activation factor (BAFF) are currently targeted in autoimmune diseases as B-cell regulators. In multiple sclerosis (MS), combined APRIL/BAFF blockade led to unexpected exacerbated inflammation in the central nervous system (CNS) of patients. Here, we investigate the role of the APRIL/BAFF axis in the CNS.METHODS:APRIL expression was analyzed in MS lesions by immunohistochemistry. The in vivo role of APRIL was assessed in the murine MS model, experimental autoimmune encephalitis (EAE). Functional in vitro studies were performed with human and mouse astrocytes.RESULTS:APRIL was expressed in lesions from EAE. In its absence, the disease was worst. Lesions from MS patients also showed APRIL expression upon infiltration of macrophages. Notably, all the APRIL secreted by these macrophages specifically targeted astrocytes. The upregulation of chondroitin sulfate proteoglycan, sometimes bearing chondroitin sulfate of type E sugar moieties, binding APRIL, in reactive astrocytes explained the latter selectivity. Astrocytes responded to APRIL by producing a sufficient amount of IL-10 to dampen antigen-specific T-cell proliferation and pathogenic cytokine secretion. Finally, an intraspinal delivery of recombinant APRIL before disease onset, shortly reduced EAE symptoms. Repeated intravenous injections of recombinant APRIL before and even at disease onset also had an effect.INTERPRETATION:Our data show that APRIL mediates an anti-inflammatory response from astrocytes in MS lesions. This protective activity is not shared with BAFF. ANN NEUROL 2019;85:406-420.© 2019 American Neurological Association.
- Subjects :
- Male
0301 basic medicine
T-Lymphocytes
Mice
chemistry.chemical_compound
0302 clinical medicine
B-Cell Activating Factor
Medicine
Mice, Knockout
Reverse Transcriptase Polymerase Chain Reaction
Chondroitin Sulfates
Middle Aged
Immunohistochemistry
Interleukin-10
3. Good health
Interleukin 10
Neurology
Adult
Aged
Animals
Astrocytes/immunology
Astrocytes/metabolism
Astrocytes/pathology
B-Cell Activating Factor/metabolism
Cell Proliferation
Chondroitin Sulfate Proteoglycans/metabolism
Chondroitin Sulfates/metabolism
Cytokines/immunology
Disease Models, Animal
Encephalomyelitis, Autoimmune, Experimental/immunology
Encephalomyelitis, Autoimmune, Experimental/metabolism
Encephalomyelitis, Autoimmune, Experimental/pathology
Female
Humans
Interleukin-10/immunology
Macrophages/pathology
Multiple Sclerosis/immunology
Multiple Sclerosis/metabolism
Multiple Sclerosis/pathology
T-Lymphocytes/immunology
Tumor Necrosis Factor Ligand Superfamily Member 13/genetics
Tumor Necrosis Factor Ligand Superfamily Member 13/metabolism
Tumor Necrosis Factor Ligand Superfamily Member 13/pharmacology
Cytokines
[SDV.IMM]Life Sciences [q-bio]/Immunology
Tumor necrosis factor alpha
medicine.symptom
Encephalomyelitis, Autoimmune, Experimental
Multiple Sclerosis
[SDV.IMM] Life Sciences [q-bio]/Immunology
Tumor Necrosis Factor Ligand Superfamily Member 13
Inflammation
03 medical and health sciences
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
B-cell activating factor
Autoimmune encephalitis
business.industry
Macrophages
Multiple sclerosis
medicine.disease
030104 developmental biology
Chondroitin Sulfate Proteoglycans
chemistry
Chondroitin sulfate proteoglycan
Astrocytes
Immunology
Cytokine secretion
Neurology (clinical)
business
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 03645134 and 15318249
- Database :
- OpenAIRE
- Journal :
- Annals of Neurology, Annals of Neurology, Wiley, 2019, 85 (3), pp.406-420. ⟨10.1002/ana.25415⟩, Annals of neurology, vol. 85, no. 3, pp. 406-420, Annals of neurology, 85(3), 406-420. John Wiley and Sons Inc., Annals of Neurology, 2019, 85 (3), pp.406-420. ⟨10.1002/ana.25415⟩
- Accession number :
- edsair.doi.dedup.....64212102082e58fcca9193ce04f096a3