Effects of CB2 Receptor Modulation on Macrophage Polarization in Pediatric Celiac Disease

Abstract

Celiac Disease (CD) represents an autoimmune disorder triggered by the exposure to gluten in genetically susceptible individuals. Recent studies suggest the involvement of macrophages in CD pathogenesis. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). The Cannabinoid Receptor 2 (CB2) has important anti-inflammatory and immunoregulatory properties. We previously demonstrated that a common CB2 functional variant, Q63R, causing CB2 reduced function, is associated with several inflammatory and autoimmune diseases The first aim of this study was to investigate the phenotype of macrophages isolated from peripheral blood of CD patients and CB2 expression. The second aim was to evaluate the effects of CB2 pharmacological modulation on CD macrophage polarization. Moreover, by an in vitro model of “immunocompetent gut” we investigated the role of CD macrophages in inducing intestinal barrier damage and the possibility to restore its functionality modulating their polarization. We found an increased expression of M1 macrophages and a CB2 reduced expression. We also demonstrated CD M1 macrophages in inducing the typical mucosal barrier damage of CD. CB2 stimulation switches macrophage polarization towards the anti-inflammatory M2 phenotype thus reducing inflammation but also limiting the epithelial dysfunction. Therefore, we suggest CB2 receptor as a possible novel therapeutic target for CD by regulating macrophages polarization and by preventing mucosal barrier damage.

A novel cuproptosis-related molecular pattern and its tumor microenvironment characterization in colorectal cancer

“…In addition, regulatory T cells act as immunosuppressive cells through many cytokines and cells. However, macrophages are known to be classified into two main phenotypes: proinflammatory and antitumor M1 macrophages and immunosuppressive M2 macrophages (58,59). M0 macrophages can be selectively polarized into M1 macrophages or M2 macrophages according to the TME characteristics.…”

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy

“…They can be present in two characterized and archetypal different phenotypes: “M1-macrophages”, or classically activated macrophages with pro-inflammatory functions, and “M2-macrophages”, or alternatively activated macrophages exerting anti-inflammatory and immunosuppressive activities [ 15 ]. The imbalance in M1/M2 ratio with a M1 prevalence can be observed in several inflammatory and autoimmune diseases [ 16 , 17 , 18 ], which thus permits to hypothesize their involvement in the pathogenesis of these diseases. Macrophages are known to express cannabinoid receptor 2 (CB2), as well as all the other peripheral cells involved in immune response [ 19 ].…”

Emerging Roles of the Iron Chelators in Inflammation

“…Also in celiac disease, an autoimmune disorder, an alteration of iron metabolism caused by its impaired inflammatory state is reported [ 45 ]. A prevalence of M1 pro-inflammatory macrophages together with an excess of intracellular iron concentration could be involved in celiac disease pathogenesis, contributing to inflammation [ 45 ].…”

“…The dysregulation of iron metabolism in IBD depends on the overactivation and production of hepcidin, derived by the increased levels of inflammatory state in IBD and, in particular, by high concentration of IL-6 [31,35,39]. Also in celiac disease, an autoimmune disorder, an alteration of iron metabolism caused by its impaired inflammatory state is reported [45]. A prevalence of M1 pro-inflammatory macrophages together with an excess of intracellular iron concentration could be involved in celiac disease pathogenesis, contributing to inflammation [45].…”