Immune thrombocytopenia (
ITP) is an autoimmune disorder characterized by antibody-mediated platelet destruction, with a complex and unclear pathogenesis. The impaired immunosuppressive capacity of mesenchymal stromal cells in
ITP patients (
ITP-MSCs) might play a role in the development of the disease. Correcting the MSC defects could represent an alternative therapeutic approach for
ITP. High-dose
dexamethasone (HD-Dexa) is the mainstay of the
ITP therapeutic regimen, although it has several side effects. We previously demonstrated a role for
cannabinoid receptor 2 (CB₂) as a mediator of anti-inflammatory and immunoregulatory properties of human MSCs. We analyzed the effects of CB₂ stimulation, with the selective agonist
JWH-133, and of Dexa alone and in combination on
ITP-MSC survival and immunosuppressive capacity. We provided new insights into the pathogenesis of
ITP, suggesting CB₂ receptor involvement in the impairment of
ITP-MSC function and confirming MSCs as responsive cellular targets of Dexa. Moreover, we demonstrated that CB₂ stimulation and Dexa attenuate apoptosis, via Bcl2 signaling, and restore the immune-modulatory properties of MSCs derived from
ITP patients. These data suggest the possibility of using Dexa in combination with
JWH-133 in
ITP, reducing its dose and side effects but maintaining its therapeutic benefits.