TY - JOUR
T1 - A proliferation-inducing ligand–mediated anti-inflammatory response of astrocytes in multiple sclerosis
AU - Baert, Laurie
AU - Benkhoucha, Mahdia
AU - Popa, Natalia
AU - Ahmed, Mashal C.
AU - Manfroi, Benoit
AU - Boutonnat, Jean
AU - Sturm, Nathalie
AU - Raguenez, Gilda
AU - Tessier, Marine
AU - Casez, Olivier
AU - Marignier, Romain
AU - Ahmadi, Mitra
AU - Broisat, Alexis
AU - Ghezzi, Catherine
AU - Rivat, Cyril
AU - Sonrier, Corinne
AU - Hahne, Michael
AU - Baeten, Dominique
AU - Vives, Romain R.
AU - Lortat-Jacob, Hugues
AU - Marche, Patrice N.
AU - Schneider, Pascal
AU - Lassmann, Hans P.
AU - Boucraut, Jose
AU - Lalive, Patrice H.
AU - Huard, Bertrand
PY - 2019/2/28
Y1 - 2019/2/28
N2 - 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;9999:1–15.
AB - 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;9999:1–15.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85061064584&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30635946
U2 - https://doi.org/10.1002/ana.25415
DO - https://doi.org/10.1002/ana.25415
M3 - Article
C2 - 30635946
SN - 0364-5134
VL - 85
SP - 406
EP - 420
JO - Annals of neurology
JF - Annals of neurology
IS - 3
ER -