Prostaglandin transporter OATP2A1/SLCO2A1 is essential for body temperature regulation during fever

Abstract

Prostaglandin E2 (PGE2 ) in the hypothalamus is a principal mediator of the febrile response. However, the role of organic anion transporting polypeptide 2A1 (OATP2A1/SLCO2A1), a prostaglandin transporter, in facilitating this response is unknown. Here, we investigated the effect of Slco2a1 deficiency on the body core temperature (Tc) and on the PGE2 concentration in hypothalamus interstitial fluid (Cisf ) and CSF (Ccsf ) of lipopolysaccharide (LPS; 100 g/kg, i.p.)-treated mice of both sexes. Slco2a1+/+ mice did not develop a febrile response. Ccsf was increased in Slco2a1-/- and Slco2a1+/+ mice, and Ccsf of Slco2a1+/+ mice was well maintained at 5 h after LPS injection (1160 pg/ml) compared with Slco2a1-/- mice (316 pg/ml). A microdialysis study revealed that Cisf peaked at 2 h after LPS injection in Slco2a1-/- mice (841 pg/ml), whereas the increase in Cisf was negligible in Slco2a1+/+ mice. The PGE2 plasma concentration in Slco2a1+/+ mice (201 pg/ml) was significantly higher than that in Slco2a1-/- mice (54 pg/ml) at 1 h after LPS injection, whereas the two groups showed similar PGE2 concentrations in the hypothalamus. Strong Oatp2a1 immunoreactivity was observed in F4/80-positive microglia and perivascular cells and in brain capillary endothelial cells. The changes in Tc and Cisf seen in LPS-injected Slco2a1-/- mice were partially attenuated in monocyte-/macrophage-specific Slco2a1+/+ (Slco2a1Fl/Fl/LysMCre/) mice. Thus, OATP2A1 facilitates the LPS-induced febrile response by maintaining a high level of Cisf, possibly by regulating PGE2 secretion from F4/80-positive glial cells and/or facilitating PGE2 transport across the blood–brain barrier. These findings suggest that OATP2A1 is a useful therapeutic target for neuroinflammation.