Eicosapentaenoic acid and 5-HEPE enhance macrophage-mediated Treg induction in mice

Abstract

Eicosapentaenoic acid (EPA) is an omega-3 fatty acid with immunomodulatory and anti-inflammatory effects. Beyond its direct effects, the metabolic products of EPA also regulate various immune responses. Animal experiments demonstrated that EPA reduces adipose inflammation in high fat diet-induced obese mouse. However, the effects of EPA on infiltrated immune cell populations in adipose tissue and underlying mechanisms remain to be elucidated. We performed flow cytometry of stromal vascular fraction of epididymal adipose tissues from C57BL/6J and ob/ob mice fed normal chow mixed with or without 5% EPA. The numbers of hematopoietic cells, including Tregs, were higher in both C57BL/6J and ob/ob mice fed EPA diet compared with control diet. EPA enhanced the induction of Tregs in co-cultures of adipose tissue macrophages (ATMs) and naïve T cells. Among EPA metabolites, 5-HEPE was the most potent inducer of Tregs. GPR119 and GPR120 are receptors for 5-HEPE and EPA, respectively, and antagonist of GPR119 blocked Treg induction by EPA in the presence of ATMs. Alox5 gene encodes 5-lipoxygenase enzyme catalyzing EPA into 5-HEPE, and inhibitor of 5-lipoxygenase down-regulated EPA-mediated induction of adipose tissue Tregs in ob/ob mice. The study findings demonstrated that both EPA and 5-HEPE enhance ATM-mediated Treg induction.

A Unique Population: Adipose-Resident Regulatory T Cells

“…Surprisingly, C57BL/6 and ob/ob mice fed with 5% Eicosapentaenoic acid mixed into chow diet had an increase in the number of Treg cells in epididymal adipose tissues compared with control mice fed with normal chow. However, only C57BL/6 mice showed lowered body and adipose tissue weight than controls ( 87 ). Recently, it was reported that oral administration of thiazolidinediones (TZDs), PPARγ agonists with insulin-sensitizing function, in HFD-fed mice enhanced the fraction and number of Treg cells specifically in epididymal adipose tissue ( 11 , 27 ).…”

Production of lipid mediators in mastitic milk of cow

“…In contrast to AA, EPA and DHA were rarely detectable in the clinical mastitic milk, while the concentrations of metabolites of the n‐3 PUFAs, such as 5‐HEPE and 18‐HEPE were increased. EPA and DHA are the essential fatty acid for mammalians and their metabolites are reported to have anti‐inflammatory and resolving role in inflammation (Bennett & Gilroy, ; Endo et al, ; Onodera et al, ). In the inflamed udder, n‐3 PUFAs may be exhausted to produce these mediators.…”

“…number of milk samples which contained target PUFA in each group (center column) and relative concentration of each PUFA substrate in subclinical and clinical mastitic milk compared with that in healthy milk (right column). EPA and DHA are the essential fatty acid for mammalians and their metabolites are reported to have anti-inflammatory and resolving role in inflammation(Bennett & Gilroy, 2016;Endo et al, 2014;Onodera et al, 2017). Abbreviations: AA, arachidonic acid; C, clinical mastitis; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; H, healthy, OEA, oleylethanolamide; PEA, palmitoylethanolamide; PUFA, polyunsaturated fatty acid; S, subclinical mastitis Nevalainen, Graham, & Scott, 2008),.…”

Allergy immunotherapy restores airway epithelial barrier dysfunction through suppressing IL-25 -induced endoplasmic reticulum stress in asthma

“…Mice spleen were removed, homogenized and filtered through a 200-mesh screen. Mononuclear cells (MCs) in splenocytes were isolated using lymphocyte ficoll 18 . The frequency of CD4 + CD25 + Foxp3 + Treg cells in MCs was measured to assess therapeutic effect of SIT.…”