Atanga, Pascal Aliihnui

ABSTRACT Brain atrophy is a common feature of numerous neurologic diseases in which the role of neuroinflammation remains ill‐defined. In this study, we evaluated the contribution of major histocompatibility complex class I molecules to brain atrophy in Theiler's murine encephalomyelitis virus (TMEV)–infected transgenic FVB mice that express the D b class I molecule. FVB/D b and wild‐type FVB mice were evaluated for changes in neuroinflammation, virus clearance, neuropathology, and development of brain atrophy via T2‐weighted MRI and subsequent 3‐dimensional volumetric analysis. Significant brain atrophy and hippocampal neuronal loss were observed in TMEV‐infected FVB/D b mice, but not in wild‐type FVB mice. Brain atrophy was observed at 1 mo postinfection and persisted through the 4‐mo observation period. Of importance, virus‐infected FVB/D b mice elicited a strong CD8 T‐cell response toward the immunodominant D b ‐restricted TMEV‐derived peptide, VP2 121–130 , and cleared TMEV from the CNS. In addition, immunofluorescence revealed CD8 T cells near virus‐infected neurons; therefore, we hypothesize that class I restricted CD8 T‐cell responses promote development of brain atrophy. This model provides an opportunity to analyze the contribution of immune cells to brain atrophy in a system where persistent virus infection and demyelination are not factors in long‐term neuropathology.—Huseby Kelcher, A. M., Atanga, P. A., Gamez, J. D., Cumba Garcia, L. M., Teclaw, S. J., Pavelko, K. D., Macura, S. I., Johnson, A. J. Brain atrophy in picornavirus‐infected FVB mice is dependent on the H‐2Db class I molecule. FASEB J. 31, 2267–2275 (2017). www.fasebj.org

ABSTRACT Inflammatory response of blood–brain barrier (BBB) endothelial cells plays an important role in pathogenesis of many central nervous system inflammatory diseases, including multiple sclerosis; however, the molecular mechanism mediating BBB endothelial cell inflammatory response remains unclear. In this study, we first observed that knockdown of neuropilin-1 (NRP1), a co-receptor of several structurally diverse ligands, suppressed interferon-γ (IFNγ)-induced C-X-C motif chemokine 10 expression and activation of STAT1 in brain microvascular endothelial cells in a Rac1-dependent manner. Moreover, endothelial-specific NRP1-knockout mice, VECadherin-Cre-ERT2/NRP1flox/flox mice, showed attenuated disease progression during experimental autoimmune encephalomyelitis, a mouse neuroinflammatory disease model. Detailed analysis utilizing histological staining, quantitative PCR, flow cytometry and magnetic resonance imaging demonstrated that deletion of endothelial NRP1 suppressed neuron demyelination, altered lymphocyte infiltration, preserved BBB function and decreased activation of the STAT1–CXCL10 pathway. Furthermore, increased expression of NRP1 was observed in endothelial cells of acute multiple sclerosis lesions. Our data identify a new molecular mechanism of brain microvascular endothelial inflammatory response through NRP1–IFNγ crosstalk that could be a potential target for intervention of endothelial cell dysfunction in neuroinflammatory diseases.