Omega‐3 and its impact on immune health:
exploring the potential of omega‐3
November 20th, 2014
Food Matters Live, London
Session: Capitalising on the immunity 'super' trend
Omega‐3 and its impact on immune health
Gerard Bannenberg
Omega‐3 and its impact on immune health
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
Omega‐3 and its impact on immune health
“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/dispensableessential fatty acids
Discovery of essential fatty acids.A. Spector and H. Kim. J. Lipid Research Nov. 10, 2014.
Omega‐3 and its impact on immune health
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.
Omega‐3 and its impact on immune health
Omega‐3 and its impact on immune health
Enders et al. New Engl. J. Med. 320, 1989
Exud
ate
prot
ein
(mg)
(ext
race
llula
r)
0 42 12 24 48 72Time (h)
2
4
6
8* *
**‡
*‡
*‡
Cel
l num
ber (
x106
)
5
10
15
20
25
0
Total exudate cellsPMNMononuclear cells
The inflammatory response : time course ‐ leukocytes and exudate protein
Pro‐inflammatory phase
Resolution phaseZymosan A‐stimulated peritonitis in mouse(1 mg i.p.)
Bannenberg et al. J. Immunol. 2005Molecular circuits of resolution: formation and actions of resolvins and protectins.
Lawrence, Willoughby, Gilroy, Nat. Rev. Immunol. 2002Anti‐inflammatory lipid mediators and insights into the resolution of inflammation.
Time
Neutrophil infiltration
Inflammation(pro‐inflammatory
phase)
Resolution(removal of neutrophilic
exudate)
Neutrophil
Microbial infection
Endothelial cell
Monocyte
Macrophage
Neutrophil adhesion to endothelium,adhesion, chemotaxis, diapedesis &activation
Neutrophil phagocytosisof microbes
Neutrophils die by apoptosis
Monocyte migration and differentiation to macrophages
Non‐phlogistic phagocytosisof apoptotic neutrophils
Macrophage egress to lymph nodes or undergo apoptosis
Cel
l num
ber
(x10
6 )
5
10
15
0 4 24 48 72 Time (h)
100%
50%
(Duration)R50 = 7.5x106
T50 = 20 h
12
I PMN=mono = 24 h
PMN
Mononuclear cells
Ri8 h
(Magnitude)max = 15 x 106
Tmax = 12 h
The resolution of acute inflammation; A definition in operative and quantitative terms
by the following Resolution Indices
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. 2005.
Omega‐3 and its impact on immune health
0
50
100
150
ng/m
ouse
0
IL-6 ++
12 24 48 722 4
Time (h)
ng/m
ouse
0
5
10
15
MIP-2 ++
JE (MCP-1)*KC (IL-8) ++
0
0.3
0.6
0.9
1.2
1.5TGF-
ng/m
ouse SDF-1 *
MIP-1 ++
TNF- ++
ng/m
ouse
0
0.5
1.0
1.5
2.0
RANTES*
GM-CSF ++
IFN- *
IL-13*
IL-10 ++
IL-4 ++
ng/m
ouse
IL-12 ++
0.025
0.050
0.075
0
Temporal profiles of cytokines and chemokines
resolution
Temporal profiles of DHA‐derived lipid mediators
DHA
17S-H(p)DHA
10,17S-docosatriene
Time (h)0
1
2
3
4 12 24 48 72
Am
ount
(ng)
per
mou
se
2
*
###
resolution
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. 2005.
Omega‐3 and its impact on immune health
Hong et al, JBC 278, 2003; Serhan, J.Immunol. 176, 2006; Yamada FASEBJ 2011
Specialized Pro‐resolving lipid Mediators ‐ SPMs
Arachidonic acid EPA DHA
Prostanoids:PGE2PGI2PGF2αPGD2
Thromboxane A212‐HHT
Leukotrienes:Leukotriene B4Cysteinyl‐leukotrienes
Lipoxins:Lipoxins (LXA4 / LXB4)
“3‐series” Prostanoids:PGE3PGI3PGF3αPGD3
TXB3Leukotriene B5
E‐series resolvins:RvE1RvE2RvE3
12‐OH‐17,18‐EpETE
D‐series resolvins:RvD1RvD2RvD3RvD4RvD5RvD6
Protectin D1 (PD1 / NPD1)10S,17S‐dihydroxylated DHA
Maresins (MaR1, MaR2)14‐Hydroxy‐sulfido‐conjugates14,20‐diHDHA
Specific SPMs are formed at defined time intervals during 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. 2013.
resolution
Lipoxin A4 Lipoxin B4
COOH
OH
OHHO OH
COOH
OHHO
Epithelia or monocytes
15-lipoxygenase 5-lipoxygenasePMN
15S-H(p)ETE Leukotriene A4
5-lipoxygenase 12-lipoxygenasePlatelets
COOH
O(O)H
PMN
OCOOH
NSAIDs
Eicosanoids:ProstaglandinsLeukotrienesThromboxane
Arachidonic acidCOOH
Cyclooxygenase
Lipoxin biosynthesis
Formation of Resolvin E1
Eicosapentaenoic acid(EPA; C20:5)
18R-HEPE
5S-hydroperoxy-18R-hydroxy-EPE
5S,12S,18R-EPE(Resolvin E1; RvE1)
acetylated-COX2 /cytochrome P450
(unknown endogenous/microbial)
5-lipoxygenase(PMN)
COOH
COOH
O(O)H
COOH
O(O)H
O(O)HCOOH
OH
OH
OH
Epoxide formationand rearrangement with incorporation
of water
Serhan, J. Exp. Med. 192, 2000
Aspirin+
+ Lipoxin A4 stableanalogue (ATLa)
0
4
8
12
16
0 4 8 12 16 20 24 28
max = 13.2x106
Tmax ~ 12 hr
Ri~12 hr
T50 ~ 24 hr
cell
num
ber (
x106
)
Time (h)
Acute Inflammation
0
4
8
12
16
0 4 8 12 16 20 24 28
Ri~13 hr
T50 ~ 24 hrR50 = 8.25x106
cell
num
ber (
x106
)
Time (h)
max = 16.5x106
Tmax ~ 11 hr+ RVE1
0
4
8
12
16
0 4 8 12 16 20 24 28
Ri~12 hr
T50 ~ 20 hr
max = 12x106
Tmax ~ 8 hr
cell
num
ber (
x106
)
Time (h)
+ protectin D1
0
4
8
12
16
0 4 8 12 16 20 24 28
Ri~6 hr
T50 ~ 11 hr
cell
num
ber (
x106
)Time (h)
max = 10x106
Tmax ~ 5 hr
Modulation of inflammation and resolutionOmega‐3 and its impact on immune health
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. 2005.
Omega‐3 and its impact on immune health
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 endogenousanti‐inflammation and the resolution of inflammation
SPMs are lipid mediators which actively regulate a concerted set of cellular actions that promote the resolution of inflammation
Inhibit• Chemotaxis• Diapedesis• Transmigration• Degranulation
Stimulate• Adherence• Chemotaxis• Non-phlogisticphagocytosis
Stimulate• Non-phlogisticphagocytosis ofapoptotic PMN PMN
Monocyte
Macrophage
SPMsInhibit• IL-12 production • Migration
Dendritic cells
Regulate• IL-8 & BPI
gene expression• NF-κB mediated
transcription
Inhibit• TNF secretion
Inhibit• Chemotaxis• Allergen-induced
trafficking
T-cells
Eosinophils
Epithelial cells
Omega-3 and its impact on immune health
LC omega‐3 and omega‐6 derived anti‐inflammatory lipid mediators function as endogenous receptor ligands
Cash et al, Drug Discovery Today 2014
Cel
l num
ber (
x106
)
5
10
15
20
25
0
Time (h)
PMN
The inflammatory response and “Immune Health”
0 42 12 24 48 72
Anti‐inflammatory
Action
Pro‐resolutionAnti‐inflammatory + resolution toxicResolution toxicAnti‐inflammatory + pro‐resolution
Redefining the importance of food and dietary components as anti-inflammatory and/or pro-resolving for immune health
- Which foods, nutrients, and diets are pro-resolving and drive resolution of inflammation?
- Which compounds or conditions interfere with resolution?
- Can we ascribe chronic inflammatory disease to defects in resolution?
Omega‐3 and its impact on immune health
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 2009.
Omega‐3 and its impact on immune health
J Dalli et al. Chem. Biol. 2013.
SPMs stimulate clearance of infections
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.
E. coli aloneE. coli + RvD1E. coli + ciprofloxacinE. coli + RvD1 + ciprofloxacin
Omega‐3 and its impact on immune health
SPMs are tissue protective
in inflammatory disease
M Arita et al. PNAS 2005Resolvin E1, an endogenous lipid mediator derived from omega‐3 eicosapentaenoic acid, protects against 2,4,6‐trinitrobenzene sulfonic acid induced colitis.
Omega‐3 and its impact on immune health
Omega‐3 and its impact on immune health
Eosinophils control the resolution of inflammation and draining lymph node hypertrophy through the proresolving mediators and CXCL13 pathway in mice. Tani, et al. FASEBJ 2014.
Specialized proresolving mediators enhance human B cell differentiation to antibody‐secreting cells. J. Immunol. 189, 2012. 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. 2014 Nov 12.
Resolution-type eosinophils
PD1, RvD1, LXA4
Lymph node
Increased B‐cell maturation and antigen‐specific antibody formation
B cell
Macrophage
CXCL13
+
migration to draining lymph node
17‐hydroxy‐DHA
+
SPMs promote adaptive immunity
SPM formation upon oral intake of its precursors EPA and 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. 2014. 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, 2014. Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN.
Omega‐3 and its impact on immune health
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
Omega‐3 and its impact on immune health
‐ 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
Omega‐3‐derived lipid mediators in the inflammatory response
The lipoxin analogue ATLa stops leukocyte infiltration in zymosan A‐stimulated peritonitis
Inhibitio
n of leukocyte
infiltration (%
)
Lipid mediators have oral bio‐availability and/or systemic actions
Stable lipoxin analogs
COOCH3
OHHO
OOH
F
ATLa 15‐epi‐16‐(p‐fluoro)‐phenoxy‐LXA4‐methyl ester
Bannenberg et al. Br. J. Pharmacol. 2004Lipoxins and novel 15‐epi‐lipoxin analogs display potent anti‐inflammatory actions after oral administration.
Omega‐3 and its impact on immune health
Dose ATLa(ng)
1.0 10 100
Gavage
0
20
40
60
80
Dose ATLa(ng)
10 100 1000
Intravenous
ATLa LXA4 LXB4
Gavage
Dose 100 ng
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
Omega‐3 and its impact on immune health
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