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 (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 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 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 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 STATEMENT

Fever 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 (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 PGE₂ transport across the blood-brain barrier.