Natalizumab exacerbates astrocytopathy in NMOSD via blockade of endothelial VCAM1–astrocytic integrin α4 interaction
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disorder of the central nervous system (CNS) that shares clinical features with multiple sclerosis (MS) but typically manifests with more severe symptoms. The presence of pathogenic IgG autoantibodies targeting aquaporin-4 (AQP4) channels on astrocytes serves as a highly specific biomarker that distinguishes NMOSD from MS. Unlike MS, NMOSD is characterized by profound astrocytic destruction and exhibits a distinct response to therapies. Notably, disease-modifying therapies (DMTs) effective in MS, including natalizumab, interferon-β, and fingolimod, not only fail to benefit NMOSD patients but may also exacerbate disease progression. The precise molecular mechanisms underlying this immunomodulator-induced exacerbation, however, remain not yet fully elucidated. Here, we demonstrate that natalizumab alleviated experimental autoimmune encephalomyelitis (EAE) while exacerbating the autoimmune astrocytopathy in an “EAE-NMOSD” mouse model, a phenomenon associated with a reduction in actively proliferating astrocytes. Through molecular and signaling pathway analyses, we identify that endothelial-derived vascular cell adhesion molecule 1 (VCAM1) activates astrocytes via integrin α4 signaling, thereby mitigating astrocytopathy in NMOSD-like mice. Furthermore, astrocyte-specific integrin α4 deficiency exacerbates astrocytopathy, and notably, natalizumab-induced disease exacerbation does not occur in integrin α4-conditional knockout (CKO) mice. Finally, pharmacological activation of astrocytes rescues natalizumab-induced damage and ameliorates demyelination in NMOSD-like mice. Collectively, our findings provide mechanistic gaps regarding the clinical phenomenon underlying natalizumab-induced NMOSD exacerbation and suggest astrocyte-targeted therapeutic strategies as a potential intervention for NMOSD.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Tingting Cui
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Qing Wen
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Zixuan An
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Jingqi Kang
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Pei Li
Department of Materials Science and Engineering, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong 999077, P. R. China
Yuechen Zeng
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Lan Lin
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Rui Gao
Guo Cheng
Luhang Dai
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Zhe Feng
Ye Gong
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Xin Zhang
Ke Li
Xiaoli Ding
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Xiaochang Xue
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Luting Yang
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University
Lei Zhang
Yaling Zhang
State Key Laboratory of Chemical Resource Engineering, College of Chemistry
Yaping Yan
Key Laboratory for Medicinal Resources and Natural Pharmaceutical Chemistry, Ministry of Education, College of Life Sciences, Shaanxi Normal University