Lenabasum, a cannabinoid type 2 receptor agonist, exerts anti-inflammatory effects in dermatomyositis

Dermatomyositis (DM) is an autoimmune disease classically affecting the skin, muscles, and lungs. Patients with DM have poor QOL, and current treatments fail to work in half of patients with DM. There is a need for an effective and safer therapeutic option. Lenabasum is a nonimmunosuppressive, nonpsychoactive cannabinoid receptor type 2 (CB2) agonist that promotes resolution of innate immune responses. The activation of CB2 reduces several proinflammatory cytokines implicated in DM. The purpose of this study was to conduct a multiplexed analysis of DM skin and PBMCs to examine the effect of lenabasum on inflammatory and itch-promoting cytokines. Our data show that lenabasum has anti-inflammatory effects, particularly on CD4+ T cells, T helper 1 cells, and myeloid cell lineages such as monocyte-derived dendritic cells. Lenabasum suppressed T helper 1-derived IL-31 and monocyte-derived dendritic cell-derived IL-31, a cytokine implicated in DM pruritus. CB2 knockdown of cells eluted from DM skin abrogated these anti-inflammatory effects. The higher CB2 expression and stronger lenabasum response in cells eluted from DM skin than from DM PBMCS indicate that local tissue environment shapes inflammatory cell behavior. Our results show that lenabasum acts through the CB2, promoting the downregulation of proinflammatory cytokines. This may explain lenabasum's greater effect on skin than in muscle in human studies.