023 Lenabasum, a cannabinoid type 2 receptor agonist, exerts anti-inflammatory effects in dermatomyositis in Th1 cells

Abstract

Dermatomyositis (DM) is a chronic, systemic autoimmune disease affecting the skin, muscle, and lungs. Lenabasum, a non-psychoactive cannabinoid type 2 receptor (CB2R) agonist, is currently being investigated as a non-immunosuppressive treatment option for DM. The activation of CB2R has been shown to reduce several key pro-inflammatory cytokines implicated in DM. Our lab has previously demonstrated via immunohistochemistry (IHC) that Lenabasum decreases CD4, IFNβ, IFNγ and IL31 expression in DM skin at 12 weeks (p<0.05), with no differences in IL4 compared to placebo (p>0.05). In this study, we then utilized multiplexed flow cytometry of leukocytes eluted from DM skin to further analyze the expression of CB2R on 12 cell lineages. When evaluating cell lineages, CD4 T helper (Th) subsets were gated on CD4+ IFNγ+ Th1 and CD4+IL4+ Th2. There was a significantly higher frequency of parent (FOP) percentage (p<0.05) of CB2R in Th1 (61.05%, n=6) versus Th2 cells (25.5%, n=6). Among myeloid cell lineages, there was greater FOP of CB2R in M2 macrophages (CD68+CD163+), CD14++CD16++ macrophages, and monocyte derived dendritic cells (moDCs; CD11c+CD14+). With 15mmol of Lenabasum, there was a trend towards a decrease of: TNFα in M2 macrophages; IFNγ and IFNβ in CD4+ Tcells; IFNβ in CD16+ cells; and IL31 in Th1 cells, CD14++CD16+ macrophages, and M2 macrophages. There was also a significant decrease in moDCs secreting IL31 with Lenabasum (p<0.01). Imaging mass cytometry of untreated DM skin demonstrated the highest IL31 MPI in moDCs. IL31 was also elevated to a lesser extent in other myeloid cell lineages. These data suggest Lenabasum may exert specific anti-inflammatory effects in DM, particularly on Th1 cells and Th1-derived IL31.