Enhancement of prostaglandin D2-D prostanoid 1 signaling reduces intestinal permeability by stimulating mucus secretion

Akane Hayashi; Naoaki Sakamoto; Koji Kobayashi; Takahisa Murata

doi:10.3389/fimmu.2023.1276852

Enhancement of prostaglandin D₂-D prostanoid 1 signaling reduces intestinal permeability by stimulating mucus secretion

Front Immunol. 2023 Oct 24:14:1276852. doi: 10.3389/fimmu.2023.1276852. eCollection 2023.

Authors

Akane Hayashi¹, Naoaki Sakamoto¹, Koji Kobayashi², Takahisa Murata^{1

2

3}

Affiliations

¹ Animal Radiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
² Food and Animal Systemics, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
³ Veterinary Pharmacology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.

Abstract

Introduction: The intestinal barrier plays a crucial role in distinguishing foods from toxins. Prostaglandin D₂ (PGD₂) is one of the lipid-derived autacoids synthesized from cell membrane-derived arachidonic acid. We previously reported that pharmacological stimulation of PGD₂ receptor, D prostanoid 1 (DP1) attenuated the symptoms of azoxymethane/dextran sodium sulfate-induced colitis and ovalbumin-induced food allergy in mouse models. These observations suggested that DP1 stimulation protects the intestinal barrier. The present study aimed to uncover the effects of DP1 stimulation on intestinal barrier function and elucidate the underlying mechanisms.

Materials and methods: Intestinal permeability was assessed in mice by measuring the transfer of orally administered fluorescein isothiocyanate-dextran (40 kDa) into the blood. The DP1 agonist BW245C (1 mg/kg) was administered 10 min prior to dextran administration. The intestinal permeability was confirmed using the ex vivo everted sac method. Tight junction integrity was evaluated in vitro by measuring the transepithelial electrical resistance (TER) in the human intestinal epithelial cell line Caco-2. Mucus secretion was assessed by observing Alcian Blue-stained intestinal sections.

Results: Pharmacological DP1 stimulation reduced intestinal permeability both in vivo and ex vivo. Immunohistochemical staining showed that DP1 was strongly expressed on the apical side of the epithelial cells. DP1 stimulation did not affect TER in vitro but induced mucus secretion from goblet cells. Mucus removal by a mucolytic agent N-acetyl-l-cysteine canceled the inhibition of intestinal permeability by DP1 stimulation.

Conclusion: These observations suggest that pharmacological DP1 stimulation decreases intestinal permeability by stimulating mucus secretion.

Keywords: D prostanoid receptor; intestinal barrier; intestinal permeability; mucin; prostaglandin D2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Caco-2 Cells
Dextrans*
Humans
Mice
Mucus / metabolism
Permeability
Prostaglandin D2 / metabolism
Prostaglandins*

Substances

Prostaglandins
Dextrans
Prostaglandin D2

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (20H05678 to TM), an Adaptable and Seamless Technology Transfer Program through Target-driven R&D (A-STEP) from the Japan Science and Technology Agency (JST, JPMJTR22UF), the Asahi Group Foundation, the Terumo Life Science Foundation. The authors declare that this study received funding from SEKISUI CHEMICAL Co. Ltd for a Research Support Program to TM. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.