The Omega-3 Postbiotic -10--15-octadecadienoic Acid Attenuates Contact Hypersensitivity in Mice Through Downregulation of Vascular Endothelial Growth Factor A

Overview

Journal Front Cell Infect Microbiol

Specialties Cell Biology
Infectious Diseases
Microbiology

Date 2024 Jun 6

PMID 38841110

Authors

Azusa Saika

Takahiro Nagatake

Shigenobu Kishino

Nahoko Kitamura

Tetsuya Honda

Koji Hosomi

Prabha Tiwari

Eri Node

Soichiro Kawai

Saki Kondo

Kei Ishida

Kenji Kabashima

Jun Ogawa

Jun Kunisawa

Affiliations

Soon will be listed here.

Abstract

Intestinal bacteria metabolize dietary substances to produce bioactive postbiotics, among which some are recognized for their role in promoting host health. We here explored the postbiotic potential of two omega-3 α-linolenic acid-derived metabolites: -10--15-octadecadienoic acid (t10,c15-18:2) and -9--15-octadecadienoic acid (c9,c15-18:2). Dietary intake of lipids rich in omega-3 α-linolenic acid elevated levels of t10,c15-18:2 and c9,c15-18:2 in the serum and feces of mice, an effect dependent on the presence of intestinal bacteria. Notably, t10,c15-18:2 mitigated skin inflammation in mice that became hypersensitive after exposure to 2,4-dinitrofluorobenzene, an experimental model for allergic contact dermatitis. In particular, t10,c15-18:2-but not c9,c15-18:2-attenuated ear swelling and edema, characteristic symptoms of contact hypersensitivity. The anti-inflammatory effects of t10,c15-18:2 were due to its ability to suppress the release of vascular endothelial growth factor A from keratinocytes, thereby mitigating the enhanced vascular permeability induced by hapten stimulation. Our study identified retinoid X receptor as a functional receptor that mediates the downregulation of skin inflammation upon treatment with t10,c15-18:2. Our results suggest that t10,c15-18:2 holds promise as an omega-3 fatty acid-derived postbiotic with potential therapeutic implications for alleviating the skin edema seen in allergic contact dermatitis-induced inflammation.

References

Hoppe A, Katsoulis-Dimitriou K, Edler H, Dudeck J, Drube S, Dudeck A . Mast cells initiate the vascular response to contact allergens by sensing cell stress. J Allergy Clin Immunol. 2020; 145(5):1476-1479.e3. DOI: 10.1016/j.jaci.2020.01.036. View

Samochocki Z, Bogaczewicz J, Sysa-Jedrzejowska A, McCauliffe D, Kontny E, Wozniacka A . Expression of vascular endothelial growth factor and other cytokines in atopic dermatitis, and correlation with clinical features. Int J Dermatol. 2015; 55(3):e141-6. DOI: 10.1111/ijd.13132. View

Lukiw W, Ottlecz A, Lambrou G, Grueninger M, Finley J, Thompson H . Coordinate activation of HIF-1 and NF-kappaB DNA binding and COX-2 and VEGF expression in retinal cells by hypoxia. Invest Ophthalmol Vis Sci. 2003; 44(10):4163-70. DOI: 10.1167/iovs.02-0655. View

Leger C, Daveloose D, Christon R, VIRET J . Evidence for a structurally specific role of essential polyunsaturated fatty acids depending on their peculiar double-bond distribution in biomembranes. Biochemistry. 1990; 29(31):7269-75. DOI: 10.1021/bi00483a016. View

Miller J, Siripurkpong P, Hawes J, Majdalawieh A, Ro H, McLeod R . The trans-10, cis-12 isomer of conjugated linoleic acid decreases adiponectin assembly by PPARgamma-dependent and PPARgamma-independent mechanisms. J Lipid Res. 2007; 49(3):550-62. DOI: 10.1194/jlr.M700275-JLR200. View

Granlund L, Juvet L, Pedersen J, Nebb H . Trans10, cis12-conjugated linoleic acid prevents triacylglycerol accumulation in adipocytes by acting as a PPARgamma modulator. J Lipid Res. 2003; 44(8):1441-52. DOI: 10.1194/jlr.M300120-JLR200. View

Honda T, Egawa G, Grabbe S, Kabashima K . Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. J Invest Dermatol. 2012; 133(2):303-15. DOI: 10.1038/jid.2012.284. View

OConnell K, OConnell Motherway M, Hennessey A, Brodhun F, Ross R, Feussner I . Identification and characterization of an oleate hydratase-encoding gene from Bifidobacterium breve. Bioengineered. 2013; 4(5):313-21. PMC: 3813531. DOI: 10.4161/bioe.24159. View

Bhushan M, McLaughlin B, Weiss J, Griffiths C . Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis. Br J Dermatol. 1999; 141(6):1054-60. DOI: 10.1046/j.1365-2133.1999.03205.x. View

10.

Moya-Camarena S, Vanden Heuvel J, Blanchard S, Leesnitzer L, Belury M . Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARalpha. J Lipid Res. 1999; 40(8):1426-33. View

11.

Apte R, Chen D, Ferrara N . VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019; 176(6):1248-1264. PMC: 6410740. DOI: 10.1016/j.cell.2019.01.021. View

12.

Boukamp P, Petrussevska R, Breitkreutz D, Hornung J, Markham A, Fusenig N . Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 1988; 106(3):761-71. PMC: 2115116. DOI: 10.1083/jcb.106.3.761. View

13.

Hagen G, Muller S, Beato M, Suske G . Sp1-mediated transcriptional activation is repressed by Sp3. EMBO J. 1994; 13(16):3843-51. PMC: 395297. DOI: 10.1002/j.1460-2075.1994.tb06695.x. View

14.

Beppu F, Hosokawa M, Tanaka L, Kohno H, Tanaka T, Miyashita K . Potent inhibitory effect of trans9, trans11 isomer of conjugated linoleic acid on the growth of human colon cancer cells. J Nutr Biochem. 2006; 17(12):830-6. DOI: 10.1016/j.jnutbio.2006.01.007. View

15.

Nagatake T, Kishino S, Urano E, Murakami H, Kitamura N, Konishi K . Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques. Mucosal Immunol. 2022; 15(2):289-300. PMC: 8866125. DOI: 10.1038/s41385-021-00477-5. View

16.

Saika A, Nagatake T, Kishino S, Park S, Honda T, Matsumoto N . 17(),18()-epoxyeicosatetraenoic acid generated by cytochrome P450 BM-3 from inhibits the development of contact hypersensitivity via G-protein-coupled receptor 40-mediated neutrophil suppression. FASEB Bioadv. 2020; 2(1):59-71. PMC: 6996328. DOI: 10.1096/fba.2019-00061. View

17.

Fujita Y, Kano K, Kishino S, Nagao T, Shen X, Sato C . Dietary cis-9, trans-11-conjugated linoleic acid reduces amyloid β-protein accumulation and upregulates anti-inflammatory cytokines in an Alzheimer's disease mouse model. Sci Rep. 2021; 11(1):9749. PMC: 8115273. DOI: 10.1038/s41598-021-88870-9. View

18.

Saika A, Nagatake T, Hirata S, Sawane K, Adachi J, Abe Y . ω3 fatty acid metabolite, 12-hydroxyeicosapentaenoic acid, alleviates contact hypersensitivity by downregulation of CXCL1 and CXCL2 gene expression in keratinocytes via retinoid X receptor α. FASEB J. 2021; 35(4):e21354. DOI: 10.1096/fj.202001687R. View

19.

Basak S, Duttaroy A . Conjugated Linoleic Acid and Its Beneficial Effects in Obesity, Cardiovascular Disease, and Cancer. Nutrients. 2020; 12(7). PMC: 7401241. DOI: 10.3390/nu12071913. View

20.

Arcondeguy T, Lacazette E, Millevoi S, Prats H, Touriol C . VEGF-A mRNA processing, stability and translation: a paradigm for intricate regulation of gene expression at the post-transcriptional level. Nucleic Acids Res. 2013; 41(17):7997-8010. PMC: 3783158. DOI: 10.1093/nar/gkt539. View