Omega 3 and its impact on immune health:

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1 Omega 3 and its impact on immune health: exploring the potential of omega 3 Gerard Bannenberg November 20 th, 2014 Food Matters Live, London Session: Capitalising on the immunity 'super' trend

2 Objectives Omega 3: A central role in the inflammatory response Understanding the actions of long chain omega 3 poly unsaturated fatty acids (LC omega 3 PUFA) in the immune system: formation and actions omega 3 derived lipid mediators Evolution in the field and why food matters

3 Omega 3 a structural descriptor of a functional group LC omega 3 PUFA: EPA eicosapentaenoic acid (C20:5) DHA docosahexaenoic acid (C22:6) EPA and DHA can be considered conditionally in/dispensable essential fatty acids Discovery of essential fatty acids. A. Spector and H. Kim. J. Lipid Research Nov. 10, 2014.

4 Is there a role for EPA and DHA in the immune system and do LC omega 3 PUFA support immune health? Historical perspectives on the impact of n 3 and n 6 nutrients on health. Bill Lands. Progress in Lipid Research 55, 2014.

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6 Enders et al. New Engl. J. Med. 320, 1989

7 The inflammatory response : time course leukocytes and exudate protein Pro inflammatory phase Cell number (x10 6 ) Resolution phase Total exudate cells PMN Mononuclear cells Zymosan A stimulated peritonitis in mouse (1 mg i.p.) 0 Exudate protein (mg) (extracellular) * * * * Time (h) * * Bannenberg et al. J. Immunol Molecular circuits of resolution: formation and actions of resolvins and protectins. Lawrence, Willoughby, Gilroy, Nat. Rev. Immunol Anti inflammatory lipid mediators and insights into the resolution of inflammation.

8 Neutrophil Microbial infection Endothelial cell Monocyte Macrophage Neutrophil infiltration Neutrophil adhesion to endothelium, adhesion, chemotaxis, diapedesis & activation Neutrophil phagocytosis of microbes Neutrophils die by apoptosis Monocyte migration and differentiation to macrophages Time Inflammation (pro inflammatory phase) Resolution (removal of neutrophilic exudate) Non phlogistic phagocytosis of apoptotic neutrophils Macrophage egress to lymph nodes or undergo apoptosis

9 (Magnitude) max = 15 x 10 6 T max = 12 h The resolution of acute inflammation; A definition in operative and quantitative terms by the following Resolution Indices % (Duration) R 50 = 7.5x10 6 Mononuclear cells Cell number (x10 6 ) 10 5 R i 8 h T 50 = 20 h I PMN=mono = 24 h PMN 50% Time (h) Molecular circuits of resolution: formation and actions of resolvins and protectins. G. Bannenberg, N. Chiang, A. Ariel, M. Arita, E. Tjonahen, KH. Gotlinger, S. Hong & CN Serhan. J. Immunol

10 Temporal profiles of cytokines and chemokines ng/mouse resolution IFN- * RANTES* IL-13* GM-CSF ++ IL-4 ++ IL ng/mouse JE (MCP-1)* KC (IL-8) ++ MIP ng/mouse IL-6 ++ ng/mouse SDF-1 * MIP-1 ++ TNF- ++ TGF IL Time (h) ng/mouse

11 Temporal profiles of DHA derived lipid mediators resolution DHA Amount (ng) per mouse # * ## 17S-H(p)DHA 10,17S-docosatriene Time (h) G. Bannenberg, N. Chiang, A. Ariel, M. Arita, E. Tjonahen, KH. Gotlinger, S. Hong & CN Serhan. Hong et al, JBC 278, 2003; Serhan, J.Immunol. 176, 2006; Yamada FASEBJ 2011Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol

12 Arachidonic acid EPA DHA Prostanoids: PGE2 PGI2 PGF2α PGD2 Thromboxane A2 12 HHT Leukotrienes: Leukotriene B4 Cysteinyl leukotrienes Lipoxins: Lipoxins (LXA4 / LXB4) 3 series Prostanoids: PGE3 PGI3 PGF3α PGD3 TXB3 Leukotriene B5 E series resolvins: RvE1 RvE2 RvE3 12 OH 17,18 EpETE D series resolvins: RvD1 RvD2 RvD3 RvD4 RvD5 RvD6 Specialized Pro resolving lipid Mediators SPMs Protectin D1 (PD1 / NPD1) 10S,17S dihydroxylated DHA Maresins (MaR1, MaR2) 14 Hydroxy sulfido conjugates 14,20 dihdha

13 Specific SPMs are formed at defined time intervals during resolution resolution J Dalli, J Winkler, R Colas, H Arnardottir, C Cheng, N. Chiang, N Petasis & CN Serhan. Resolvin D3 and aspirin triggered resolvin D3 are potent immunoresolvents. Chem. Biol

14 Lipoxin biosynthesis Arachidonic acid COOH Cyclooxygenase NSAIDs Eicosanoids: Prostaglandins Leukotrienes Thromboxane 15-lipoxygenase Epithelia or monocytes COOH 5-lipoxygenase PMN O COOH 15S-H(p)ETE O(O)H Leukotriene A 4 5-lipoxygenase PMN 12-lipoxygenase Platelets HO OH OH COOH COOH OH HO OH Lipoxin A 4 Lipoxin B 4

15 Formation of Resolvin E1 Aspirin + acetylated-cox2 / cytochrome P 450 (unknown endogenous/microbial) COOH COOH Eicosapentaenoic acid (EPA; C20:5) O(O)H 18R-HEPE 5-lipoxygenase (PMN) O(O)H COOH Epoxide formation and rearrangement with incorporation of water OH COOH O(O)H OH OH 5S-hydroperoxy- 18R-hydroxy-EPE 5S,12S,18R-EPE (Resolvin E1; RvE1) Serhan, J. Exp. Med. 192, 2000

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17 Modulation of inflammation and resolution Acute Inflammation max = 16.5x10 6 T max ~ 11 hr + RVE1 max = 12x10 6 T max ~ 8 hr cell number (x10 6 ) Ri ~13 hr T 50 ~ 24 hr R 50 = 8.25x Time (h) cell number (x10 6 ) Ri ~12 hr T 50 ~ 20 hr Time (h) + Lipoxin A4 stable analogue (ATLa) cell number (x10 6 ) max = 13.2x10 6 T max ~ 12 hr Ri ~12 hr T 50 ~ 24 hr Time (h) + protectin D1 cell number (x10 6 ) max = 10x10 6 T max ~ 5 hr Ri ~6 hr T 50 ~ 11 hr Time (h) G. Bannenberg, N. Chiang, A. Ariel, M. Arita, E. Tjonahen, KH. Gotlinger, S. Hong & CN Serhan. Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol

18 Important indications 1. Resolution of inflammation is not a passive process 2. Resolution can be activated 3. Anti inflammation is not the same as pro resolution LC omega 3 derived lipid mediators play an important role in endogenous anti inflammation and the resolution of inflammation

19 Omega-3 and its impact on immune health SPMs are lipid mediators which actively regulate a concerted set of cellular actions that promote the resolution of inflammation Dendritic cells Inhibit IL-12 production Migration SPMs T-cells Inhibit TNF secretion Macrophage Stimulate Non-phlogistic phagocytosis of apoptotic PMN Monocyte Stimulate Adherence Chemotaxis Non-phlogistic phagocytosis PMN Inhibit Chemotaxis Diapedesis Transmigration Degranulation Eosinophils Inhibit Chemotaxis Allergen-induced Regulate trafficking IL-8 & BPI gene expression NF-κB mediated transcription Epithelial cells

20 LC omega 3 and omega 6 derived antiinflammatory lipid mediators function as endogenous receptor ligands Cash et al, Drug Discovery Today 2014

21 The inflammatory response and Immune Health PMN Cell number (x10 6 ) Redefining the importance of food and dietary components as anti-inflammatory and/or proresolving for immune health Action Time (h) Anti inflammatory Pro resolution Anti inflammatory + resolution toxic Resolution toxic Anti inflammatory + pro resolution - Which foods, nutrients, and diets are proresolving and drive resolution of inflammation? - Which compounds or conditions interfere with resolution? - Can we ascribe chronic inflammatory disease to defects in resolution?

22 SPMs stimulate phagocytosis No FITC zymosan FITC zymosan RvE1 (10 nm) without RvE1 T. Ohira, M Arita, K Omori, A Recchiuti, T. van Dyke & CN Serhan. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. JBC J Dalli et al. Chem. Biol

23 SPMs stimulate clearance of infections E. coli alone E. coli + RvD1 E. coli + ciprofloxacin E. coli + RvD1 + ciprofloxacin N. Chiang, G Fredman, F Bäckhed, S h, T Vickery, B Schmidt & CN Serhan. Infection regulates pro resolving mediators that lower antibiotic requirements. Nature 2010.

24 SPMs are tissue protective in inflammatory disease M Arita et al. PNAS 2005 Resolvin E1, an endogenous lipid mediator derived from omega 3 eicosapentaenoic acid, protects against 2,4,6 trinitrobenzene sulfonic acid induced colitis.

25 SPMs promote adaptive immunity Resolution-type eosinophils Macrophage CXCL13 + PD1, RvD1, LXA4 migration to draining lymph node B cell 17 hydroxy DHA + Lymph node Increased B cell maturation and antigen specific antibody formation Eosinophils control the resolution of inflammation and draining lymph node hypertrophy through the proresolving mediators and CXCL13 pathway in mice. Tani, et al. FASEBJ Specialized proresolving mediators enhance human B cell differentiation to antibody secreting cells. J. Immunol. 189, Ramon S, Gao F, Serhan CN, Phipps RP. The specialized proresolving mediator 17 HDHA enhances the antibody mediated immune response against influenza virus: A new class of adjuvant? Ramon S, et al J. Immunol Nov 12.

26 SPM formation upon oral intake of its precursors EPA and DHA Formation of lipid mediators from a single oral dose of EPA/DHA Activation of whole blood phagocytic activity after a single oral dose of EPA/DHA Increase of EPA derived hydroxy, epoxy and dihydroxy fatty acid levels in human plasma after a single dose of long chain omega 3 PUFA. Prostaglandins Other Lipid Mediat Schuchardt JP, Schneider I, Willenberg I, Yang J, Hammock BD, Hahn A, Schebb NH. Identification and signature profiles for pro resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol. 307, Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN.

27 Omega 3 derived lipid mediators in the inflammatory response Transcellular biosynthesis permits local biosynthesis under specific conditions (context dependent cell cell interactions) Receptor mediated anti inflammatory and resolution activating actions Endogenous agonists for regulating the inflammatory response

28 Lipid mediators have oral bio availability and/or systemic actions Stable lipoxin analogs ATLa 15 epi 16 (p fluoro) phenoxy LXA 4 methyl ester OH HO O OH COOCH 3 F The lipoxin analogue ATLa stops leukocyte infiltration in zymosan A stimulated peritonitis Inhibition of leukocyte infiltration (%) Intravenous Dose ATLa (ng) Gavage Dose ATLa (ng) Gavage ATLa LXA4 LXB4 Dose 100 ng Bannenberg et al. Br. J. Pharmacol Lipoxins and novel 15 epi lipoxin analogs display potent anti inflammatory actions after oral administration.

29 Acknowledgments: Organizers of Food Matters Live The Serhan laboratory Centre for Experimental Therapeutics & Reperfusion Injury, Brigham & Women s Hospital / HMS Boston (MA), USA Solutex GC (Madrid, Spain) GOED Global Organization for EPA and DHA

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