**4. Mechanisms of action of omega-3 fatty acids in endometrial cells**

The first known anti-inflammatory mechanism of omega-3 fatty acids was the formation of specialized pro-resolving mediators (SPMs) derived from DHA. The enzymatic oxygenation of DHA via 12−/15-lipoxygenase (LOX) and 5-LOX leads to the formation of the D-series resolvins (RvD1, RvD2, RvD3, RvD4, RvD5, and RvD6), neuroprotectins/protectins, and maresins in different cells [10, 66], and resolvins have a potent effect on leukocyte migration and also reduce production of pro-inflammatory cytokines [67]. All those evidences have been obtained in different cellular types, but in the uterus or endometrial cells, there are not yet studies about formation of SPM.

Two more recent mechanisms have been described in macrophages and endothelial cells: (1) binding of DHA to FFA4 receptor/β-arrestin and inhibition of TAK1/NF-κB, thus reducing synthesis of pro-inflammatory factors, and (2) inhibition of NLRP3 inflammasome. FFA4 receptor is a G-protein-coupled receptor with high affinity by DHA described first in the intestine and macrophages. Recent studies evidenced the presence of FFA4 receptor in the human, mouse, and bovine endometrium [11, 12]. After ligand binding, FFA4 receptor couples to β-arrestin2, which is followed by receptor endocytosis and inhibition of TAB1-mediated activation of TAK1, a protein activated after inflammatory stimuli such as LPS, which

induce signaling through the NF-κB pathway, thus reducing TNF-α, IL-6, and MCP-1 [68, 69]. Other studies have proposed omega-3 fatty acids to reduce the NLRP3 inflammasome activation [70–73]. The first evidence proposed two mechanisms dependent on FFA4 receptor to the reduction of inflammasome activation: first, DHA stimulation caused FFA4 receptor internalization through β-arrestin2, which reduced the initial inflammasome priming step by suppressing the nuclear translocation of NF-κB, and second, DHA enhanced autophagy, thereby reducing inflammasome complex formation or presenting inflammasome components for destruction [73]. Then, it was demonstrated that DHA reduced NLRP3 inflammasome expression in hepatocytes [70].

In the endometrium, only two lines of evidences about potential mechanisms of action of omega-3 have been studied. In human stromal cells, FFA4 receptor promoted decidualization through the upregulation of the GLUT1-mediated glucose uptake and glucose-6-phosphate dehydrogenase-mediated pentose-phosphate pathway [11]. In mice, FFA4 receptor protects LPS or RU486-induced abortion [11]. In summary, omega-3 fatty acids via FFA4 receptor increase ERK1/ERK2 and AMPK signaling and upregulate FOXO1 and GLUT1 expression, which increases glucose uptake and activates the pentose-phosphate pathway, promoting decidualization and maintenance of pregnancy. In addition, it was also shown that FFA4 receptor upregulates the expression of chemokines and cytokines such as CXCL12, TGFβ, and IL-15 [11]. In bovine endometrial cells, it was evidenced the presence of mRNA and protein of FFA4 receptor as well as an increase of intracellular calcium mobilization induced by DHA or a synthetic agonist (TUG891) of FFA4 receptor, which was inhibited by AH7614, a FFA4 receptor antagonist [12]. Also, DHA reduced NF-κB activation and PGE2 production induced by LPS; however, AH7614 did not modify these effects, suggesting that other mechanisms would be involved in the anti-inflammatory effect of DHA, which should be studied [12].

### **5. Perspectives in health and diseases**

Until now, omega-3 fatty acids have been only used as dietary supplements, or DHA-rich diet has been recommended by their beneficial effects for health. However, although the mechanism of action of DHA has begun to be elucidated, it has not been recommended yet as an anti-inflammatory drug. The recent studies have described several possible anti-inflammatory mechanisms and propose omega-3 fatty acids as potential treatment for spontaneous abortion for its effect on decidualization and the maintenance of pregnancy [11]. Also, omega-3 fatty acids would be useful for the prevention and treatment of endometriosis because this disorder is characterized by a chronic inflammation [44, 46, 47]. In veterinary medicine, omega-3 fatty acids have potential use in fertility of dairy cows. Omega-3- rich supplements have been associated with improved reproductive performance, and the recent evidence of the presence of FFA4 receptor in the endometrium [12] could contribute to understand the mechanism as omega-3 fatty acids exert its effects, and open new possibilities for the prevention and treatment of the endometrial inflammation associated with infectious diseases, such as metritis or endometritis.

### **6. Conclusions**

Omega-3 fatty acids have anti-inflammatory effects through different mechanisms, described in macrophages and endothelial cells: formation of SPMs, activation of the FFA4 receptor, inhibition of TAK1/NF-κB activation, and inflammasome

**219**

**Author details**

Maria A. Hidalgo1

Valdivia, Chile

\*, Marcelo Ratto2

\*Address all correspondence to: mahidalgo@uach.cl

provided the original work is properly cited.

and Rafael A. Burgos1

1 Institute of Pharmacology and Morphophysiology, University Austral of Chile,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Institute of Animal Science, University Austral of Chile, Valdivia, Chile

*Beneficial Effect of Omega-3 Fatty Acids on Immune and Reproductive Endometrial Function*

inhibition. These mechanisms have not yet been demonstrated in the endometrium, but the presence of the FFA4 receptor and the inhibition of NF-κB, PGE2, and PGF2α suggest that similar anti-inflammatory mechanism could occur in the endometrium. Furthermore, omega-3 fatty acids could be useful for the treatment of disorders such as endometriosis or metritis/endometritis, as well as the preven-

Funded by Fondo Nacional de Desarrollo Científico y Tecnológico (Fondecyt No.

*DOI: http://dx.doi.org/10.5772/intechopen.89351*

**Acknowledgements**

**Conflict of interest**

1151047).

tion of spontaneous abortion and improvement of fertility.

The authors declare no conflict of interest.

*Beneficial Effect of Omega-3 Fatty Acids on Immune and Reproductive Endometrial Function DOI: http://dx.doi.org/10.5772/intechopen.89351*

inhibition. These mechanisms have not yet been demonstrated in the endometrium, but the presence of the FFA4 receptor and the inhibition of NF-κB, PGE2, and PGF2α suggest that similar anti-inflammatory mechanism could occur in the endometrium. Furthermore, omega-3 fatty acids could be useful for the treatment of disorders such as endometriosis or metritis/endometritis, as well as the prevention of spontaneous abortion and improvement of fertility.
