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

Prostaglandin E 2 (PGE 2 ) 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 PGE 2 concentration in hypothalamus interstitial fluid (C isf ) and cerebrospinal fluid (C csf ) of lipopolysaccharide (LPS, 100 μg/kg i.p.)-treated mice of both sexes. Slco2a1 -/- mice did not develop a febrile response. C csf was increased in Slco2a1 +/+ and Slco2a1 -/- mice, and C csf of Slco2a1 -/- was well maintained at 5 hr after LPS injection (1160 pg/mL), compared to Slco2a1 +/+ (316 pg/mL). A microdialysis study revealed that C isf peaked at 2 hr after LPS injection in Slco2a1 +/+ (841 pg/mL), whereas the increase in C isf was negligible in Slco2a1 -/- mice. The PGE 2 plasma concentration in Slco2a1 -/- mice (201 pg/mL) was significantly higher than that in Slco2a1 +/+ mice (54 pg/mL) at 1 hr after LPS injection, whereas the two groups showed similar PGE 2 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 of Tc and C isf seen in LPS-injected Slco2a1 +/+ mice were partially attenuated in monocyte/macrophage-specific Slco2a1 -/- ( Slco2a1 Fl/Fl / LysM Cre/+ ) mice. Thus, OATP2A1 facilitates the LPS-induced febrile response by maintaining a high level of C isf , possibly by regulating PGE 2 secretion from F4/80-positive glial cells and/or facilitating PGE 2 transport across the blood-brain barrier. These findings suggest that OATP2A1 is a useful therapeutic target for neuroinflammation. SIGNIFICANCE STATEMENT Fever is a physiological response caused by pyrogen-induced release of prostaglandin E 2 (PGE 2 ) in the hypothalamus, which plays a central role in regulating the set-point of body temperature. However, it is unclear whether the prostaglandin transporter, OATP2A1/ SLCO2A1 , is involved in this response. We show here that LPS-induced fever is associated with increased PGE 2 concentration in hypothalamus interstitial fluid (C isf ), but not in cerebrospinal fluid (C csf ), by means of a microdialysis study in global Slco2a1 -knockout mice and monocyte/macrophage-specific Slco2a1 -knockout mice. The results suggest that OATP2A1 serves as a regulator of C isf in F4/80-positive glial cells. OATP2A1 was detected immunohistochemically in brain capillary endothelial cells, and therefore may also play a role in PGE 2 transport across the blood-brain barrier.