RT Journal Article SR Electronic T1 Prostaglandin transporter OATP2A1/SLCO2A1 is essential for body temperature regulation during fever JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 3276-17 DO 10.1523/JNEUROSCI.3276-17.2018 A1 Nakamura, Yoshinobu A1 Nakanishi, Takeo A1 Shimada, Hiroaki A1 Shimizu, Junya A1 Aotani, Rika A1 Maruyama, Shio A1 Higuchi, Kei A1 Okura, Takashi A1 Deguchi, Yoshiharu A1 Tamai, Ikumi YR 2018 UL http://www.jneurosci.org/content/early/2018/05/21/JNEUROSCI.3276-17.2018.abstract AB 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 cerebrospinal fluid (Ccsf) of lipopolysaccharide (LPS, 100 μg/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-/- was well maintained at 5 hr after LPS injection (1160 pg/mL), compared to Slco2a1+/+ (316 pg/mL). A microdialysis study revealed that Cisf peaked at 2 hr after LPS injection in Slco2a1+/+ (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 hr 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 of 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.SIGNIFICANCE STATEMENTFever is a physiological response caused by pyrogen-induced release of prostaglandin E2 (PGE2) 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 PGE2 concentration in hypothalamus interstitial fluid (Cisf), but not in cerebrospinal fluid (Ccsf), 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 Cisf in F4/80-positive glial cells. OATP2A1 was detected immunohistochemically in brain capillary endothelial cells, and therefore may also play a role in PGE2 transport across the blood-brain barrier.