A proliferation-inducing ligand-mediated anti-inflammatory response of astrocytes in multiple sclerosis.

Abstract

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.

• Authors: Laurie Baert, Mahdia Benkhoucha, Natalia Popa, Mashal C Ahmed, Benoit Manfroi, Jean Boutonnat, Nathalie Sturm, Gilda Raguenez, Marine Tessier, Olivier Casez, Romain Marignier, Mitra Ahmadi, Alexis Broisat, Catherine Ghezzi, Cyril Rivat, Corinne Sonrier, Michael Hahne, Dominique Baeten, Romain R Vives, Hugues Lortat-Jacob, Patrice N Marche, Pascal Schneider, Hans P Lassmann, Jose Boucraut, Patrice H Lalive, Bertrand Huard
• Journal: Annals of neurology (Ann Neurol) Vol. 85 Issue 3 Pg. 406-420 (03 2019) ISSN: 1531-8249 [Electronic] United States
• PMID: 30635946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 American Neurological Association.

Chemical References

• B-Cell Activating Factor
• Chondroitin Sulfate Proteoglycans
• Cytokines
• Tumor Necrosis Factor Ligand Superfamily Member 13
• Interleukin-10
• Chondroitin Sulfates

Topics

• Adult
• Aged
• Animals
• Astrocytes (immunology, metabolism, pathology)
• B-Cell Activating Factor (metabolism)
• Cell Proliferation
• Chondroitin Sulfate Proteoglycans (metabolism)
• Chondroitin Sulfates (metabolism)
• Cytokines (immunology)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (immunology, metabolism, pathology)
• Female
• Humans
• Immunohistochemistry
• Interleukin-10 (immunology)
• Macrophages (pathology)
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Multiple Sclerosis (immunology, metabolism, pathology)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocytes (immunology)
• Tumor Necrosis Factor Ligand Superfamily Member 13 (genetics, metabolism, pharmacology)