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Research Articles, Neurobiology of Disease

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

Yoshinobu Nakamura, Takeo Nakanishi, Hiroaki Shimada, Junya Shimizu, Rika Aotani, Shio Maruyama, Kei Higuchi, Takashi Okura, Yoshiharu Deguchi and Ikumi Tamai
Journal of Neuroscience 21 May 2018, 3276-17; DOI: https://doi.org/10.1523/JNEUROSCI.3276-17.2018
Yoshinobu Nakamura
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
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Takeo Nakanishi
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
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Hiroaki Shimada
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
2Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan
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Junya Shimizu
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
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Rika Aotani
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
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Shio Maruyama
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
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Kei Higuchi
3Faculty of Pharma-Sciences, Teikyo University, Tokyo 173-8605, Japan
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Takashi Okura
3Faculty of Pharma-Sciences, Teikyo University, Tokyo 173-8605, Japan
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Yoshiharu Deguchi
3Faculty of Pharma-Sciences, Teikyo University, Tokyo 173-8605, Japan
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Ikumi Tamai
1Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan.
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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 (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 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 (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.

Footnotes

  • The authors declare no competing financial interests.

  • We thank Drs. Ken-ichi Hosoya and Shin-ichi Akanuma at University of Toyama for their constructive comments and technical advice, and for providing antibodies to detect Oatp2a1. We also thank Dr. Eiichi Hinoi and Ms. Maika Okamoto for their assistance for measuring colorectal temperature. This research was carried out with the support of Grants-in-Aid for Scientific Research (KAKENHI, 15H04755 and 15K15181) from the Japan Society for the Promotion of Science. We thank Mr. Richard Steele (B. Sc.) for his careful reading.

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Prostaglandin transporter OATP2A1/SLCO2A1 is essential for body temperature regulation during fever
Yoshinobu Nakamura, Takeo Nakanishi, Hiroaki Shimada, Junya Shimizu, Rika Aotani, Shio Maruyama, Kei Higuchi, Takashi Okura, Yoshiharu Deguchi, Ikumi Tamai
Journal of Neuroscience 21 May 2018, 3276-17; DOI: 10.1523/JNEUROSCI.3276-17.2018

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Prostaglandin transporter OATP2A1/SLCO2A1 is essential for body temperature regulation during fever
Yoshinobu Nakamura, Takeo Nakanishi, Hiroaki Shimada, Junya Shimizu, Rika Aotani, Shio Maruyama, Kei Higuchi, Takashi Okura, Yoshiharu Deguchi, Ikumi Tamai
Journal of Neuroscience 21 May 2018, 3276-17; DOI: 10.1523/JNEUROSCI.3276-17.2018
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