Fig. 1

Molecular CB2R-mediated lenabasum pathway adapted from Burnstein¹³. In CD4⁺ T cell specifically, lenabasum binds to CB2R and activates caspase-3. This leads to CD4⁺ T cell apoptosis. As a general leukocyte pathway, lenabasum binds to CB2R and activates cPLA2 to break down phospholipids to AA. The pathway branches into a COX2-mediated and 15LOX1-mediated pathway. The COX2 pathway begins with the conversion of AA via COX2 into PGH₂, which is subsequently converted to PGD₂ by PGDs. PGD₂ is converted to 15d-PGJ₂ through a non-enzymatic spontaneous reaction. 15d-PGJ₂ inhibits NLRP3 and leads to inflammation resolution. The latter 15LOX1 pathway converts AA into LXA₄ via 15LOX1, which can bind to the FPR2/ALX receptor on a nearby cell and lead to inflammation resolution (although this LXA₄-FPR2/ALX interaction is not definitive). FPR2/ALX exerts its anti-inflammatory effects by inhibiting IRAK1 and TRAF6. IRAK1 and TRAF6 are downstream effectors of TLR activation and ultimately lead to the production of INFβ via IRF5 and IFNγ via NFkB and IL-12^39,40,41,42. Created with BioRender.com. cPLA2: Cytosolic phospholipase A2; AA: Arachidonic acid; COX2: Cyclooxygenase-2; 15LOX1: 15-lipoxygenase-1; PGH₂: Prostaglandin H2; PGDs: Prostaglandin D2 synthase; PGD₂: Prostaglandin D2; 15d-PGJ₂: 15-Deoxy-Δ -12,14-prostaglandin J2; NLRP3: Nod-like receptor protein 3; LXA₄: Lipoxin A4; FPR2/ALX: Formyl peptide receptor 2.