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. 2019 Nov 22;11(12):2868.
doi: 10.3390/nu11122868.

Dietary Omega-3 Fatty Acid Dampens Allergic Rhinitis via Eosinophilic Production of the Anti-Allergic Lipid Mediator 15-Hydroxyeicosapentaenoic Acid in Mice

Kento Sawane  1   2   3 , Takahiro Nagatake  2 , Koji Hosomi  2 , So-Ichiro Hirata  2   4 , Jun Adachi  5 , Yuichi Abe  6 , Junko Isoyama  5 , Hidehiko Suzuki  2 , Ayu Matsunaga  2 , Satoshi Fukumitsu  1   7 , Kazuhiko Aida  1 , Takeshi Tomonaga  5 , Makoto Arita  8   9   10 , Jun Kunisawa  2   3   4   11   12
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V体育2025版 - Dietary Omega-3 Fatty Acid Dampens Allergic Rhinitis via Eosinophilic Production of the Anti-Allergic Lipid Mediator 15-Hydroxyeicosapentaenoic Acid in Mice

Kento Sawane et al. Nutrients. .

Abstract

The metabolism and generation of bioactive lipid mediators are key events in the exertion of the beneficial effects of dietary omega-3 fatty acids in the regulation of allergic inflammation VSports手机版. Here, we found that dietary linseed oil, which contains high amounts of alpha-linolenic acid (ALA) dampened allergic rhinitis through eosinophilic production of 15-hydroxyeicosapentaenoic acid (15-HEPE), a metabolite of eicosapentaenoic acid (EPA). Lipidomic analysis revealed that 15-HEPE was particularly accumulated in the nasal passage of linseed oil-fed mice after the development of allergic rhinitis with the increasing number of eosinophils. Indeed, the conversion of EPA to 15-HEPE was mediated by the 15-lipoxygenase activity of eosinophils. Intranasal injection of 15-HEPE dampened allergic symptoms by inhibiting mast cell degranulation, which was mediated by the action of peroxisome proliferator-activated receptor gamma. These findings identify 15-HEPE as a novel EPA-derived, and eosinophil-dependent anti-allergic metabolite, and provide a preventive and therapeutic strategy against allergic rhinitis. .

Keywords: PPAR; eosinophil; lipid metabolism; nasal allergy; omega-3 fatty acids V体育安卓版. .

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Conflict of interest statement (VSports注册入口)

The authors declare no conflict of interest.

"V体育安卓版" Figures

Figure 1
Figure 1
Dietary linseed oil reduces allergic rhinitis responses in mice. Mice were maintained on a diet containing 4% soybean oil (Soy) or linseed oil (Lin). After 2 months, ovalbumin (OVA)-induced allergic rhinitis was induced, and the sneezing rate was calculated. Data are from three independent experiments (n = 13). Center values indicate medians. Statistical significance was calculated by using the Mann–Whitney U test.
Figure 2
Figure 2
Dietary fatty acid is reflected in the fatty acid composition of the nasal passages of mice. (A–C) The OVA-induced allergic rhinitis model was applied to mice maintained on a diet containing 4% soybean oil (Soy) or linseed oil (Lin). Mice were challenged intranasally with OVA. Cells were collected from nasal passages, and the levels of (A) alpha-linolenic acid (ALA), (B) eicosapentaenoic acid (EPA), and (C) docosahexaenoic acid (DHA) in the cells were analyzed by using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). Data are from two independent experiments (n = 7). Center values indicate medians.
Figure 3
Figure 3
Induction of allergic rhinitis influences fatty acid metabolism in nasal passages. (A–E) EPA-derived fatty acid metabolites including (A) 18-hydroxyeicosapentaenoic acid (HEPE), (B) 15-HEPE, (C) 12-HEPE, (D) 5-HEPE, and (E) 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) in nasal passages were analyzed by using LC–MS/MS. Data are from two independent experiments (n = 7). Center values indicate medians. Statistical significance between two groups was calculated by using the Mann–Whitney U test.
Figure 4
Figure 4
Nasal administration of 15-HEPE dampens allergic rhinitis. (A) Mice were nasally treated with 15-HEPE or vehicle (0.5% EtOH) before challenge in an allergic rhinitis model. Sneezing rates were calculated. Data are from two independent experiments (n = 8–10). Center values indicate medians. Statistical significance was calculated by using one-way ANOVA followed by Dunn’s Kruskal–Wallis Multiple Comparisons. (B) Allergic rhinitis was induced in mice during days 1 through 4. From day 5 through 10, 15-HEPE or mock treatment (0.5% EtOH PBS) was nasally administered 5 min before OVA challenge. Then the sneezing rate was calculated on days 4 through 10. Data are from three independent experiments (n = 11 or 12). Data are expressed as the mean ± SEM. Statistical significance was calculated by using the Mann–Whitney U test.
Figure 5
Figure 5
Eosinophils infiltrate the nasal passages upon the development of allergic rhinitis and produce 15-HEPE and eosinophil inhibition aggravates allergic rhinitis in linseed oil-fed mice. (A) PD146176, an inhibitor of 15-LOX, was injected into mice fed a linseed oil diet, and sneezing rates were calculated after the induction of allergic rhinitis. Data are from two independent experiments (n = 8). Center values indicate medians. Statistical significance was calculated by using the Mann–Whitney U test. (B–D) After the induction of allergic rhinitis, the numbers of (B) eosinophils, (C) neutrophils, and (D) mast cells in the nasal passage were calculated based on the total cell number and Flow cytometry data. Data are from three independent experiments (n = 9 or 10). Center values indicate medians. Statistical significance was calculated by using the Mann–Whitney U test. (E) Quantitative PCR analysis was performed to measure Alox15 mRNA expression in neutrophils and eosinophils isolated from nasal passages. Data are expressed as the mean ± SEM (n = 8 or 9). Statistical significance was calculated by using the Mann–Whitney U test. (F) Bone marrow-derived neutrophils and eosinophils were stimulated with 2 μM calcium ionophore in the presence of 1 μM EPA or ARA. After 30 min, the 15-HEPE level in the supernatant was analyzed by using LC–MS/MS. The panel shows representative data from two experiments with similar results (n = 4). Data are expressed as the mean ± SEM. Statistical significance was calculated by using the Mann–Whitney U test. (G–I) A mixture of anti-IL-5 antibody and anti-CCL11 antibody was injected into mice fed a linseed oil diet. Rat-IgG1 isotype was used as an isotype control. Allergic rhinitis was induced and (G) the sneezing rate, (H) eosinophil number in the NP, and (I) 15-HEPE level in the NP were analyzed. Data are from two independent experiments (n = 8). Center values indicate medians. Statistical significance was calculated by using the Mann–Whitney U test.
Figure 6
Figure 6
The 15-HEPE interacts with peroxisome proliferator-activated receptor gamma (PPARγ) and inhibits mast cell degranulation. (A) In vitro degranulation of mast cells was induced in the presence or absence of 15-HEPE in vitro. Degranulation was determined by CD63 expression by using FACS. Data are from two independent experiments (n = 4 for DNP-BSA-untreated groups and n = 8 for dinitrophenyl [DNP]-BSA-treated groups) and expressed as the mean ± SEM. Statistical significance was calculated by using one-way ANOVA followed by Tukey’s Multiple Comparisons. (B) Mast cells, eosinophils, epithelial cells, and neutrophils were isolated from mice NP and Pparg gene expression was assessed. Data are from two independent experiments (n = 8) and are expressed as the mean ± SEM. (C) GW9662, an antagonist of PPARγ, was injected into mice with allergic rhinitis 30 min before 15-HEPE administration. Sneezing rates were calculated. Data are from two independent experiments (n = 8). Center values indicate medians. Statistical significance was calculated by using one-way ANOVA followed by Dunn’s Kruskal–Wallis Multiple Comparisons.
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