Neuregulin1 modulation of experimental autoimmune encephalomyelitis (EAE)

Abstract

Neuregulin1 (NRG1) is a differentiation factor that regulates glial development, survival, synaptogenesis, axoglial interactions, and microglial activation. We previously reported that a targeted NRG1 antagonist (HBD-S-H4) given intrathecally, reduces inflammatory microglial activation in a spinal cord pain model and a neurodegenerative disease mouse model in vivo, suggesting that it may have effects in neuroninflammatory and neuronal disorders. We hypothesized that expression of HBD-S-H4 in the central nervous system (CNS) could reduce disease severity in experimental autoimmune encephalomyelitis (EAE), a widely used animal model for multiple sclerosis (MS). In the present study, we generated tetO-HBD-S-H4, a single transgenic (Tg) mouse line in, which the fusion protein in expressed in the brain, resulting in reduction of disease severity in both male and female mice when compared to sex- and age-matched wild type littermates. We also generated GFAP-tTA:tetO-HBD-S-H4 double Tg mice, which express this fusion protein in the brain and the spinal cord, they displayed sex differences in the reduction of disease severity. In healthy mice, expression of HBD-S-H4 in the CNS does not result in any significant neurological or other overt phenotypes. In myelin oligodendrocyte glycoprotein (MOG)-induced EAE, female double Tg mice show delayed disease onset and reduced disease severity compared to male double Tg as well as wild type littermates. In male double Tg mice, the levels of HBD-S-H4 gene expression negatively correlates with disease severity and increased microglia associated genes' expression. In conclusion, expression of neuregulin antagonist in the brain and spinal cord protects females but not males, suggesting a complex interplay between NRG1 and sex difference in EAE that may be associated with microglia-mediated inflammation. This study provides important information for understanding the heterogeneity of disease pathology and the therapeutic potential of targeting microglial activation in male and female MS patients.

Keywords: Experimental autoimmune encephalomyelitis; NRG1 antagonist; Neuregulin1; Sex difference.