Hematopoietic monoamine oxidase A deficiency exacerbates neuroinflammation and demyelination in female but not male mice with experimental autoimmune encephalomyelitis.

INTRODUCTION

Monoamine oxidase A (Mao A) is a mitochondrial enzyme responsible for the degradation of monoaminergic neurotransmitters. While pharmacological inhibition of Mao A has been reported to improve outcomes in experimental autoimmune encephalomyelitis (EAE), the role of Mao A in immune cells on disease progression was unknown.

METHODS

To address this question, we generated mice with conditional Mao A deletion restricted to hematopoietic cells (Mao ALeuko -/-), including circulating immune cells, and induced EAE by immunizing the mice with the MOG35-55 peptide. Disease severity, ataxia, inflammation, and demyelination were assessed.

RESULTS AND DISCUSSION: Mao ALeuko -/- female mice exhibited significantly accelerated weight loss, worsened ataxia, and a 2.2-fold increase in EAE severity compared with controls. Histological analyses revealed increased inflammation and enhanced demyelination in the lumbar spinal cords of Mao ALeuko -/- mice. Immunohistochemistry revealed increased IBA-1+ and CD68+ staining in the spinal cord, consistent with enhanced microglia and macrophage accumulation and activation and exacerbated neuroinflammation. However, no differences in CD3+ T-cells levels were observed between female Mao ALeuko -/- and Vav-i Cretg/wt EAE mice. These effects were restricted to female mice. No significant differences were observed in disease course or pathology between male Mao ALeuko -/- and control mice. This study identified hematopoietic Mao A as a novel critical regulator of neuroimmune crosstalk, with loss of Mao A function exacerbating inflammation, demyelination, and neurological deficits in female but not male EAE mice.