Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E2 synthesis in the brain and their behavioral relevance

Xiang Nie,Masakazu Shinohara,Tomoyuki Furuyashiki,Akira Kakizuka,Shiho Kitaoka,Shuh Narumiya

doi:10.1038/s41598-019-54082-5

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https://doi.org/10.1038/s41598-019-54082-5

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Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E2, 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 PGE2 synthesis in the brain and whether TLR2/4 are involved in the PGE2 synthesis remain unknown. Using mice lacking TLR2 and TLR4 in combination, here we show that social defeat stress (SDS) induced the PGE2 synthesis in subcortical, but not cortical, tissues in a TLR2/4-dependent manner. It is known that PGE2 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 PGE2 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 PGE2 synthesis in subcortical tissues. Furthermore, systemic administration of JZL184, an MAGL inhibitor, abolished repeated SDS-induced social avoidance. These results suggest that SDS induces PGE2 synthesis in subcortical regions of the brain via the MAGL-COX pathway in a TLR2/4-dependent manner, thereby leading to social avoidance.

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Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness
Whereas PGE2 signaling is crucial for repeated social defeat stress (SDS)-induced behavioral changes, how SDS increases the PGE2 synthesis in the brain remains unknown
Our findings indicate that monoacylglycerol lipase (MAGL) and COX mediate SDS-induced PGE2 synthesis in subcortical tissues, and that TLR2/4 is involved in their expression after repeated SDS

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Inflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E2, 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. Systemic administration of JZL184, an MAGL inhibitor, abolished repeated SDS-induced social avoidance These results suggest that SDS induces PGE2 synthesis in subcortical regions of the brain via the MAGL-COX pathway in a TLR2/4-dependent manner, thereby leading to social avoidance. Meta-analyses have shown that treatment with non-steroidal anti-inflammatory drugs (NSAIDs), especially celecoxib, that inhibit PG synthesis www.nature.com/scientificreports has therapeutic effects in depressive patients[10,11,12] These observations suggest a crucial role of PGE2 in the pathology of depression. Genetic deletion or pharmacological inhibition of COX1 abolishes repeated SDS-induced social avoidance[13] These findings suggest that the COX1-PGE2-EP1 pathway is crucial for repeated SDS-induced behavioral changes. Whether and how TLR2/4 are involved in SDS-induced PGE2 synthesis in the brain needs to be investigated

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