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Blockade of Proteinase-Activated Receptor 2 (Par2) Attenuates Neuroinflammation in Experimental Autoimmune Encephalomyelitis Publisher Pubmed



Eftekhari R1, 2, 3, 7, 8 ; Ewanchuk BW4, 5, 7 ; Rawji KS3, 7 ; Yates RM4, 5, 7 ; Noorbakhsh F7, 8 ; Kuipers HF3, 6, 7 ; Hollenberg MD1, 2, 7
Authors

Source: Journal of Pharmacology and Experimental Therapeutics Published:2024


Abstract

Proteinase-activated receptor-2 (PAR2), which modulates inflammatory responses, is elevated in the central nervous system 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 palmitoyl-RSSAMDENSEKKRKSAIK-amide (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 central nervous system. Moreover, P2pal-18S decreases granulocyte-macrophage colony-stimulating factor (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. Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.
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