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

Abstract

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.

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

“…Inhibiting the fatty acid desaturase SCD or its yeast ortholog OLE1 reduces levels of oleic acid and rescues α-synuclein toxicity in model organisms (Fanning et al, 2018;Vincent et al, 2018). Slco2a1 is a prostaglandin receptor expressed on microglia and endothelial cells that may play a role in neuroinflammation (Nakamura et al, 2018 [Deng, Xiu, & Jankovic, 2015]).…”

Membrane Transporters Contributing to PGE₂ Distribution in Central Nervous System

“…RT-PCR confirmed mRNA expression of rat Oatp2a1 in brain capillary-rich fraction as well as whole brain. 27) Our laboratory reported Oatp2a1 immunoreactivity in mouse brain capillaries, 28) and Oatp2a1 was immunolocalized predominantly 40) Br, 39,46) Eye, 46,99) Ki and Li 39)…”

“…Taogoshi et al reported that PGE 1 transport across the BBB is inhibited in the presence of bromocresol green, digoxin, or taurocholate by in situ rat brain perfusion technique. 27) Bromocresol green is a well-known inhibitor of OATP2A1. RT-PCR confirmed mRNA expression of rat Oatp2a1 in brain capillary-rich fraction as well as whole brain.…”

“…Taogoshi et al 27) reported that both digoxin and taurocholate are substrates of rat Oatp1a4/Slco1a2 (a.k.a. Oatp2), implying a contribution of rOatp1a4 to PGE 2 entry to the brain from blood across the BBB.…”

Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene

“…Lysozyme (Lys) M-cre mice and Villin (V)-cre mice were obtained from RIKEN Bioresource Centre (RRID:IMSR_ RBRC02302) and Jackson laboratory (B6.Cg-Tg(Vil1-cre)1000Gum/J), respectively. Slco2a1 fl/fl mice were crossed with LysM-cre mice and V-cre mice to generate mice with specific Slco2a1 deletion in macrophages (Slco2a1 ΔMP ) 48 and intestinal epithelial cells (Slco2a1 ΔIEC ). Sex-and age-matched WT mice (C57BL/6), obtained from Charles River Japan Inc. (Atsugi, Japan), and sex-and age-matched littermate LysM-cre − ;V-cre − ;Slco2a1 fl/fl mice were used as controls for Slco2a1 −/− mice and Slco2a1 ΔMP Slco2a1 ΔIEC mice, respectively.…”