Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E(2) synthesis in the brain and their behavioral relevance

Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E(2), an arachidonic acid-derived lipid mediator, and innate immune receptors Toll-like receptor (TLR) 2/4 are crucial for repeated stress-induced behavioral changes in rodents. However, how the stress induces PGE(2) synthesis in the brain and whether TLR2/4 are involved in the PGE(2) synthesis remain unknown. Using mice lacking TLR2 and TLR4 in combination, here we show that social defeat stress (SDS) induced the PGE(2) synthesis in subcortical, but not cortical, tissues in a TLR2/4-dependent manner. It is known that PGE(2) in the brain is mainly derived by monoacylglycerol lipase (MAGL)-mediated conversion of endocannabinoid 2-arachidonoylglycerol to free-arachidonic acid, a substrate for cyclooxygenase (COX) for PGE(2) synthesis. We found that TLR2/4 deletion reduced the mRNA expression of MAGL and COX1 in subcortical tissues after repeated SDS. Perturbation of MAGL and COX1 as well as COX2 abolished SDS-induced PGE(2) synthesis in subcortical tissues. Furthermore, systemic administration of JZL184, an MAGL inhibitor, abolished repeated SDS-induced social avoidance. These results suggest that SDS induces PGE(2) synthesis in subcortical regions of the brain via the MAGL-COX pathway in a TLR2/4-dependent manner, thereby leading to social avoidance.