Long chain polyunsaturated fatty acids and inflammation Philip Calder Professor of Nutritional Immunology University of Southampton

Calder et al. (2009) Brit. J. Nutr. 101, S1-S45 Adhesion Chemoattractants Vasoactive mediators Local injury Systemic effects (incl. inflammation) BLOODSTREAM TISSUE Rolling Diapedesis Inflammatory cytokines Activated leukocyte Inflammatory cytokines Inflammatory eicosanoids Reactive species Calder et al. (2009) Brit. J. Nutr. 101, S1-S45

Diseases or conditions that involve inflammation Rheumatoid arthritis Crohn’s disease Ulcerative colitis Cystic fibrosis Psoriasis Lupus Type-1 diabetes Childhood asthma Adult asthma Allergic diseases Atopic diseases COPD Atherosclerosis Acute cardiovascular events Response to surgery Trauma & sepsis Neurodegenerative diseases Some cancers Body wasting Obesity …….

What have fatty acids got to do with inflammation? Fatty acid nutrition could influence metabolite and/or hormone concentrations that in turn influence inflammation Fatty acid nutrition could influence other factors (e.g. oxidised LDL; oxidative stress) that in turn influence inflammation Direct pro- or anti-inflammatory effects via surface or intracellular “fatty acid receptors” Effects mediated via changes in inflammatory cell membrane phospholipids

=> Fatty acids differentially affect inflammation/immunity via cell surface (TLR4, GPR120) and intracellular (PPAR-g) receptors

of inflammatory cell phospholipids Altered fatty acid supply Altered composition of inflammatory cell phospholipids Membrane alterations: rafts; order; trafficking Signal transduction pathways leading to gene expression Lipid mediators Altered inflammatory cell phenotype Altered inflammatory response

Fish oil-derived long chain w-3 PUFAs exert anti-inflammatory effects by inhibiting production of arachidonic acid-derived eicosanoids

EPA is also a substrate for eicosanoid synthesis Arachidonic acid EPA 2-series PGs 4-series LTs 3-series PGs 5-series LTs “STRONG” “WEAK”

Altered (patho)physiology (less inflammatory phenotype) w-3 fatty acid exposure Receptors Membrane composition Fluidity Raft assembly Substrates for eicosanoids, resolvins etc. Signals Cell responses Altered (patho)physiology (less inflammatory phenotype)

Summary Inflammation underlies many common conditions and diseases Fatty acids can influence inflammation acting through cell surface and intracellular receptors/sensors that control inflammatory gene expression Human inflammatory cells typically contain a relatively high amount of arachidonic acid -> precursor of inflammatory eicosanoids w-3 PUFAs from fish oil are readily incorporated into inflammatory cells Fatty acid composition of inflammatory cells affects membrane fluidity, membrane raft formation, signal transduction processes leading to gene expression, and the pattern of lipid and peptide mediators produced Through these effects fatty acids can affect inflammatory cell responses and inflammatory processes Fish oil (w-3 PUFAs) exerts anti-inflammatory actions in vivo that may be associated with improved patient outcome

Conclusions Fatty acid composition of inflammatory cells influences their function Arachidonic acid, EPA and DHA contents seem to be important Mechanisms by which fatty acids affect inflammation are many and complex Long chain w-3 PUFAs are anti-inflammatory There is a theoretical basis, supported by much pre-clinical science, for clinical benefit from increased long chain w-3 PUFA supply in various patient groups Dose (of w-3 fatty acid) is important