Proteinase-activated receptor 2 modulates neuroinflammation in experimental autoimmune encephalomyelitis and multiple sclerosis

The proteinase-activated receptors (PARs) are widely recognized for their modulatory properties of inflammation and neurodegeneration. We investigated the role of PAR₂ in the pathogenesis of multiple sclerosis (MS) in humans and experimental autoimmune encephalomyelitis (EAE) in mice. PAR₂ expression was increased on astrocytes and infiltrating macrophages in human MS and murine EAE central nervous system (CNS) white matter (P < 0.05). Macrophages and astrocytes from PAR₂ wild-type (WT) and knockout (KO) mice exhibited differential immune gene expression with PAR₂ KO macrophages showing significantly higher interleukin 10 production after lipopolysaccharide stimulation (P < 0.001). PAR₂ activation in macrophages resulted in the release of soluble oligodendrocyte cytotoxins (P < 0.01). Myelin oligodendrocyte glycoprotein–induced EAE caused more severe inflammatory gene expression in the CNS of PAR₂ WT animals (P < 0.05), together with enhanced T cell proliferation and interferon γ production (P < 0.05), compared with KO littermates. Indeed, PAR₂ WT animals showed markedly greater microglial activation and T lymphocyte infiltration accompanied by worsened demyelination and axonal injury in the CNS compared with their PAR₂ KO littermates. Enhanced neuropathological changes were associated with a more severe progressive relapsing disease phenotype (P < 0.001) in WT animals. These findings reveal previously unreported pathogenic interactions between CNS PAR₂ expression and neuroinflammation with ensuing demyelination and axonal injury.