Cannabinoid Receptor 2 (CB2) in Macrophages: A Promising Clinical Target for Immune Disorders

Macrophages are essential for immune homeostasis, playing crucial roles in immune responses from initiation to resolution. They trigger acute inflammation to promote elimination of pathogens and regulate excessive immune reactions to prevent chronic inflammation and autoimmune diseases. Consequently, macrophage dysfunction contributes to the progression of many disorders that involve inflammation. Cannabinoid Receptor 2 (CB2) has emerged as a promising therapeutic target due to its role in regulating macrophage-mediated immune functions, including via modulation of cytokine secretion, migration, phagocytosis, and polarisation. CB2 activation can produce beneficial outcomes via suppressing macrophage-mediated inflammatory pathways in animal models for various diseases that involve acute or chronic central or peripheral inflammation, whereas blocking CB2 may have utility when macrophage polarisation to a "resolving" phenotype is deleterious, such as in tumour-associated macrophages. However, despite abundant promising preclinical results, the relatively few CB2-selective agonists tested in clinical trials to date have exhibited limited efficacy. Here, we provide an overview of the roles of macrophages in health and disease, thoroughly review in vitro and in vivo preclinical findings on CB2-mediated modulation of macrophage function, summarise current progress in clinical trials for CB2-targeted compounds, and discuss approaches for addressing current challenges in ongoing efforts toward developing safe and effective CB2-targeted therapeutics.