Prostaglandin Transporter OATP2A1/ SLCO2A1 Is Essential for Body Temperature Regulation during Fever

• Published in: The Journal of neuroscience Vol. 38; no. 24; pp. 5584 - 5595
• Main Authors: Nakamura, Yoshinobu, Nakanishi, Takeo, Shimada, Hiroaki, Shimizu, Junya, Aotani, Rika, Maruyama, Shio, Higuchi, Kei, Okura, Takashi, Deguchi, Yoshiharu, Tamai, Ikumi
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 13.06.2018
• Subjects: Body temperature; Brain; Cerebrospinal fluid; Endothelial cells; Fever; Glial cells; Hypothalamus; Immunoreactivity; Inflammation; Injection; Lipopolysaccharides; Macrophages; Mice; Microdialysis; Microglia; Monocytes; Organic anion transporting polypeptide; Prostaglandin E2; Rodents; Therapeutic applications; Thermoregulation; OATP2A1; fever; macrophage; prostaglandin E2; hypothalamus; transporter
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.3276-17.2018

Prostaglandin E (PGE ) in the hypothalamus is a principal mediator of the febrile response. However, the role of organic anion transporting polypeptide 2A1 (OATP2A1/ ), a prostaglandin transporter, in facilitating this response is unknown. Here, we investigated the effect of deficiency on the body core temperature (Tc) and on the PGE concentration in hypothalamus interstitial fluid ( ) and CSF ( ) of lipopolysaccharide (LPS; 100 μg/kg, i.p.)-treated mice of both sexes. mice did not develop a febrile response. was increased in and mice, and of mice was well maintained at 5 h after LPS injection (1160 pg/ml) compared with mice (316 pg/ml). A microdialysis study revealed that peaked at 2 h after LPS injection in mice (841 pg/ml), whereas the increase in was negligible in mice. The PGE plasma concentration in mice (201 pg/ml) was significantly higher than that in mice (54 pg/ml) at 1 h after LPS injection, whereas the two groups showed similar PGE 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 seen in LPS-injected mice were partially attenuated in monocyte-/macrophage-specific ( / ) mice. Thus, OATP2A1 facilitates the LPS-induced febrile response by maintaining a high level of , possibly by regulating PGE secretion from F4/80-positive glial cells and/or facilitating PGE transport across the blood-brain barrier. These findings suggest that OATP2A1 is a useful therapeutic target for neuroinflammation. Fever is a physiological response caused by pyrogen-induced release of prostaglandin E (PGE ) 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/ is involved in this response. We show here that LPS-induced fever is associated with increased PGE concentration in hypothalamus interstitial fluid ( ), but not in CSF ( ), by means of a microdialysis study in global -knock-out mice and monocyte-/macrophage-specific -knock-out mice. The results suggest that OATP2A1 serves as a regulator of in F4/80-positive glial cells. OATP2A1 was detected immunohistochemically in brain capillary endothelial cells and, therefore, may also play a role in PGE transport across the blood-brain barrier.