Abstract

Proteinase-activated receptor-2 (PAR2), which modulates inflammatory responses, is elevated in the central nervous system (CNS) in multiple sclerosis (MS) and in its murine model, experimental autoimmune encephalomyelitis (EAE). In PAR2-null mice, disease severity of EAE is markedly diminished. We therefore tested whether inhibiting PAR2 activation in vivo might be a viable strategy for the treatment of MS. Using the EAE model, we show that a PAR2 antagonist, the pepducin P2pal-18S, attenuates EAE progression by affecting immune cell function. P2pal-18S treatment markedly diminishes disease severity and reduces demyelination, as well as the infiltration of T-cells and macrophages into the CNS. Moreover, P2pal-18S decreases GM-CSF production and T cell activation in cultured splenocytes and prevents macrophage polarization in vitro. We conclude that PAR2 plays a key role in regulating neuroinflammation in EAE and that PAR2 antagonists represent promising therapeutic agents for treating MS and other neuroinflammatory diseases.

Significance Statement Proteinase-activated receptor-2 (PAR2) modulates inflammatory responses and is increased in multiple sclerosis (MS) lesions. We show that the PAR2 antagonist P2pal-18S reduces disease in the murine EAE model of MS by inhibiting T cell and macrophage activation and infiltration into the CNS, making it a potential treatment for MS.