Endogenously Synthesized n-3 fatty Acids in fat-1 Transgenic Mice Suppresses B Cell Activation

Da-Hee Kim; So-Hyun Park; Sang-Myeong Lee

doi:10.4167/jbv.2022.52.4.184

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2022 Vol.52, Issue 4 Preview Page

Original Article

Endogenously Synthesized n-3 fatty Acids in fat-1 Transgenic Mice Suppresses B Cell Activation

31 December 2022. pp. 184-193

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Abstract

n-3 Polyunsaturated fatty acids (PUFAs) have been suggested as a preventive or therapeutic strategy for autoimmune or inflammatory diseases via the modulation of the activation, differentiation, and effector functions of various immune cells, especially T cells and macrophages. Despite the importance of B cells in the pathogenesis of autoimmune diseases, few studies have demonstrated their effect on B cells. In this study, we investigated the possible effects of n-3 PUFAs on B cell activation, differentiation, and isotype switching in fat-1 transgenic mice, which can convert n-6 PUFAs to n-3 PUFAs via n-3 desaturase derived from Caenorhabditis elegans. Fat-1 mice were fed a corn oil-rich diet for at least 4 weeks to increase the probability of converting n-6 PUFAs to n-3 PUFAs. Splenic B cells were then isolated, followed by stimulation with Toll-like receptor 4 or B cell receptor (BCR). Our results showed that increased n-3 PUFA levels in B cells by fat-1 overexpression inhibited B cell proliferation, cytokine secretion, such as interleukin (IL)-6, IL-10, tumor necrosis factor-α, plasma cell differentiation, and Ig isotype switching/secretion. These effects are possibly due to the suppression of Syk, Src, and AKT activation in B cells from fat-1 mice, as well as NF-κB. Collectively, our results suggest that fat-1 expression attenuates B cell responses, and n-3 PUFA supplementation can be a possible strategy to treat pathological conditions in which B cells play a key role.

Keywords

N-3 PUFAs

Fat-1

B cell

Plasma cells

Immunoglobulin

References

Ruzickova J, Rossmeisl M, Prazak T, Flachs P, Sponarova J, Veck M, et al. Omega-3 PUFA of marine origin limit diet-induced obesity in mice by reducing cellularity of adipose tissue. Lipids 2004;39:1177-85. 10.1007/s11745-004-1345-915736913

Murff HJ, Shu XO, Li H, Yang G, Wu X, Cai H, et al. Dietary polyunsaturated fatty acids and breast cancer risk in Chinese women: a prospective cohort study. Int J Cancer 2011;128:1434-41. 10.1002/ijc.2570320878979PMC3086389

Storlien LH, Kraegen EW, Chisholm DJ, Ford GL, Bruce DG, Pascoe WS. Fish oil prevents insulin resistance induced by high-fat feeding in rats. Science 1987;237:885-8. 10.1126/science.33033333303333

Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002;106:2747-57. 10.1161/01.CIR.0000038493.65177.9412438303

Albracht-Schulte K, Kalupahana NS, Ramalingam L, Wang S, Rahman SM, Robert-McComb J, et al. Omega-3 fatty acids in obesity and metabolic syndrome: a mechanistic update. J Nutr Biochem 2018;58:1-16. 10.1016/j.jnutbio.2018.02.01229621669PMC7561009

Gutiérrez S, Svahn SL, Johansson ME. Effects of omega-3 fatty acids on immune cells. Int J Mol Sci 2019;20:5028 . 10.3390/ijms2020502831614433PMC6834330

Stulnig TM. Immunomodulation by polyunsaturated fatty acids: mechanisms and effects. 2003;132:310-21. 10.1159/00007489814707462

Kang JX. Fat-1 transgenic mice: a new model for omega-3 research. Prostaglandins Leukot Essent Fatty Acids 2007;77:263-7. 10.1016/j.plefa.2007.10.01018042365PMC2211362

Spychalla JP, Kinney AJ, Browse J. Identification of an animal ω-3 fatty acid desaturase by heterologous expression in Arabidopsis. Proc Natl Acad SciU S A 1997;94:1142-7. 10.1073/pnas.94.4.11429037020PMC19758

Kang JX, Wang J, Wu L, Kang ZB. Transgenic mice: fat-1 mice convert n-6 to n-3 fatty acids. Nature 2004;427:504. 10.1038/427504a14765186

Nowak J, Weylandt KH, Habbel P, Wang J, Dignass A, Glickman JN, et al. Colitis-associated colon tumorigenesis is suppressed in transgenic mice rich in endogenous n-3 fatty acids. Carcinogenesis 2007;28:1991-5. 10.1093/carcin/bgm16617634405

Taha AY, Huot PS, Reza-López S, Prayitno NR, Kang JX, Burnham WM, et al. Seizure resistance in fat‐1 transgenic mice endogenously synthesizing high levels of omega‐3 polyunsaturated fatty acids. J Neurochem 2008;105:380-8. 10.1111/j.1471-4159.2007.05144.x18036191

Weylandt KH, Krause LF, Gomolka B, Chiu CY, Bilal S, Nadolny A, et al. Suppressed liver tumorigenesis in fat-1 mice with elevated omega-3 fatty acids is associated with increased omega-3 derived lipid mediators and reduced TNF-α. Carcinogenesis 2011;32:897-903. 10.1093/carcin/bgr04921421544PMC3106436

Mayer K, Kiessling A, Ott J, Schaefer MB, Hecker M, Henneke I, et al. Acute lung injury is reduced in fat-1 mice endogenously synthesizing n-3 fatty acids. Am J Respir Crit Care Med 2009;179:474-83. 10.1164/rccm.200807-1064OC19136374PMC2654977

Weylandt KH, Nadolny A, Kahlke L, Köhnke T, Schmöcker C, Wang J, et al. Reduction of inflammation and chronic tissue damage by omega-3 fatty acids in fat-1 transgenic mice with pancreatitis. Biochim Biophys Acta 2008;1782:634-41. 10.1016/j.bbadis.2008.08.01118832028PMC2614880

Jang HY, Lim K, Lee SM, Park BH. Effects of n‐3 PUFA on the CD 4+ type 2 helper T‐cell‐mediated immune responses in Fat‐1 mice. Mol Nutr Food Res 2014;58:365-75. 10.1002/mnfr.20130019424019303

Woo SJ, Lim K, Park SY, Jung MY, Lim HS, Jeon MG, et al. Endogenous conversion of n-6 to n-3 polyunsaturated fatty acids attenuates K/BxN serum-transfer arthritis in fat-1 mice. J Nutr Biochem 2015;26:713-20. 10.1016/j.jnutbio.2015.01.01125910895

Jang HY, Koo JH, Lee SM, Park BH. Atopic dermatitis-like skin lesions are suppressed in fat-1 transgenic mice through the inhibition of inflammasomes. Exp Mol Med 2018;50:1-9. 10.1038/s12276-018-0104-3

Calder PC, Carr AC, Gombart AF, Eggersdorfer M. Optimal nutritional status for a well-functioning immune system is an important factor to protect against viral infections. Nutrients 2020;12:1181. 10.3390/nu1204118132340216PMC7230749

Kim JY, Lim K, Kim KH, Kim JH, Choi JS, Shim SC. N-3 polyunsaturated fatty acids restore Th17 and Treg balance in collagen antibody-induced arthritis. PLoS One 2018;13:e0194331. 10.1371/journal.pone.019433129543869PMC5854360

Kim W, Barhoumi R, McMurray DN, Chapkin RS. Dietary fish oil and DHA down-regulate antigen-activated CD4+ T-cells while promoting the formation of liquid-ordered mesodomains. Br J Nutr 2014;111:254-60. 10.1017/S000711451300244423962659PMC4327854

Monk JM, Jia Q, Callaway E, Weeks B, Alaniz RC, McMurray DN, et al. Th17 cell accumulation is decreased during chronic experimental colitis by (n-3) PUFA in Fat-1 mice. J Nutr 2012;142:117-24. 10.3945/jn.111.14705822131549PMC3237233

Fillatreau S. B cells and their cytokine activities implications in human diseases. Clin Immunol 2018;186:26-31 . 10.1016/j.clim.2017.07.02028736271PMC5844600

Corneth OBJ, Neys SFH, Hendriks RW. Aberrant B Cell Signaling in Autoimmune Diseases. Cell 2022;11:3391. 10.3390/cells1121339136359789PMC9654300

Musette P, Bouaziz JD. B cell modulation strategies in autoimmune diseases: new concepts. Front Immunol 2018;9:622. 10.3389/fimmu.2018.0062229706952PMC5908887

Hermaszewski RA, Webster AD. Primary hypogammaglobulinaemia: a survey of clinical manifestations and complications. Q J Med 1993;86:31-42.

Rockett BD, Salameh M, Carraway K, Morrison K, Shaikh, SR. n-3 PUFA improves fatty acid composition, prevents palmitate-induced apoptosis, and differentially modifies B cell cytokine secretion in vitro and ex vivo. J Lipid Res 2010;51:1284-97. 10.1194/jlr.M00085120071694PMC3035492

Verlengia R, Gorjão R, Kanunfre CC, Bordin S, de Lima TM, Martins EF, et al. Effects of EPA and DHA on proliferation, cytokine production, and gene expression in Raji cells. Lipids 2004;39: 857-64. 10.1007/s11745-004-1307-215669761

Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Allergy Clin Immunol 2013;131:959-71. 10.1016/j.jaci.2013.01.04623465663

Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014;5:520. 10.3389/fimmu.2014.0052025368619PMC4202688

Schultz CL, Coffman RL. Control of isotype switching by T cells and cytokines. Curr Opin Immunol 1991;3:350-4. 10.1016/0952-7915(91)90037-21910615

Whitmore AC, Prowse DM, Haughton G, Arnold LW. Ig isotype switching in B lymphocytes. The effect of T cell-derived interleukins, cytokines, cholera toxin, and antigen on isotype switch frequency of a cloned B cell lymphoma. Int Immunol 1991;3:95-103. 10.1093/intimm/3.1.952049338

de Matos OG, Amaral SS, Pereira da Silva PE, Perez DA, Alvarenga DM, Ferreira AV, et al. Dietary supplementation with omega-3-PUFA-rich fish oil reduces signs of food allergy in ovalbumin-sensitized mice. Clin Dev Immunol 2012;2012:236564. 10.1155/2012/23656422162714PMC3227513

Chen Z, Wang JH. How the Signaling Crosstalk of B Cell Receptor (BCR) and Co-Receptors Regulates Antibody Class Switch Recombination: A New Perspective of Checkpoints of BCR Signaling. Front Immunol 2021;12:663443. 10.3389/fimmu.2021.66344333841447PMC8027318

Oh DY, Walenta E, Akiyama TE, Lagakos WS, Lackey D, Pessentheiner AR, et al. A Gpr120-Selective Agonist Improves Insulin Resistance and Chronic Inflammation. Nat Med 2014;20:942-7. 10.1038/nm.361424997608PMC4126875

Novak TE, Babcock TA, Jho DH, Helton WS, Espat NJ. NF-kappa B inhibition by omega-3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription. Am J Physiol Lung Cell Mol Physiol 2003;284:L84-9. 10.1152/ajplung.00077.200212388359

Williams-Bey Y, Boularan C, Vural A, Huang NN, Hwang IY, Shan-Shi C, et al. Omega-3 free fatty acids suppress macrophage inflammasome activation by inhibiting NF-κB activation and enhancing autophagy. PLoS One 2014;9:e97957. 10.1371/journal.pone.009795724911523PMC4049592

Li X, Bi X, Wang S, Zhang Z, Li F, Zhao AZ. Therapeutic Potential of ω-3 Polyunsaturated Fatty Acids in Human Autoimmune Diseases. Front Immunol 2019;10:2241. 10.3389/fimmu.2019.0224131611873PMC6776881

Weise C, Hilt K, Milovanovic M, Ernst D, Rühl R, Worm M. Inhibition of IgE production by docosahexaenoic acid is mediated by direct interference with STAT6 and NFκB pathway in human B cells. J Nutr Biochem 2011;22:269-75. 10.1016/j.jnutbio.2010.02.00420576420

Information

Publisher :The Korean Society for Microbiology and The Korean Society of Virology
Publisher(Ko) :대한미생물학회‧대한바이러스학회
Journal Title :JOURNAL OF BACTERIOLOGY AND VIROLOGY
Volume : 52
No :4
Pages :184-193
Received Date : 2022-12-09
Revised Date : 2022-12-19
Accepted Date : 2022-12-20
DOI :https://doi.org/10.4167/jbv.2022.52.4.184

JOURNAL OF BACTERIOLOGY AND VIROLOGY ISSN:1598-2467(Print) 2093-0429(Online)

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