Omega-3 fatty acids, lipid rafts, and T cell signaling

Abstract

n-3 polyunsaturated fatty acids (PUFA) have been shown in many clinical studies to attenuate inflammatory responses. Although inflammatory responses are orchestrated by a wide spectrum of cells, CD4(+) T cells play an important role in the etiology of many chronic inflammatory diseases such as inflammatory bowel disease and obesity. In light of recent concerns over the safety profiles of non-steroidal anti-inflammatory drugs (NSAIDs), alternatives such as bioactive nutraceuticals are becoming more attractive. In order for these agents to be accepted into mainstream medicine, however, the mechanisms by which nutraceuticals such as n-3 PUFA exert their anti-inflammatory effects must be fully elucidated. Lipid rafts are nanoscale, dynamic domains in the plasma membrane that are formed through favorable lipid-lipid (cholesterol, sphingolipids, and saturated fatty acids) and lipid-protein (membrane-actin cytoskeleton) interactions. These domains optimize the clustering of signaling proteins at the membrane to facilitate efficient cell signaling which is required for CD4(+) T cell activation and differentiation. This review summarizes novel emerging data documenting the ability of n-3 PUFA to perturb membrane-cytoskeletal structure and function in CD4(+) T cells. An understanding of these underlying mechanisms will provide a rationale for the use of n-3 PUFA in the treatment of chronic inflammation.

Keywords: Lipid rafts; Omega-3 fatty acids; T cell activation; T cell differentiation.

Figure 1

Proposed mechanisms by which n-3 PUFA modulate adaptive immune responses by A) modulating lipid-lipid interactions in the plasma membrane; and B) altering plasma membrane lipid-protein interactions by decreasing PI(4,5)P₂ level, thereby lowering the recruitment of actin-binding proteins and suppressing actin cytoskeleton remodeling. Consequently, incorporation of n-3 PUFA into the plasma membrane increase the size and/or stability of the mesoscale lipid rafts and physiologically. This translates into suppressed CD4⁺ T cell activation and differentiation. Red highlight indicates liquid ordered lipid rafts; Blue indicates bulk membrane.

Figure 2

Immunological synapse at the A) cellular; and B) biochemical level. When CD4⁺ T cells recognize cognate antigen presented by the antigen presenting cell, an immunological synapse is formed at the cellular level. At the biochemical level, major lipidomic and proteomic rearrangement occurs to propagate T cell activation. At the lipidomic level, lipids associated with lipid rafts are found to coalesce at the immunological synapse (represented in red). Adhesion molecules, such as LFA-1, are important for the stabilization of the immunological synapse, while CD45, which is required to terminate T cell activation, is excluded from the immunological synapse. Additionally, the actin cytoskeleton is important for T cell activation by stabilizing the immunological synapse.

Figure 3

Proposed mechanism by which n-3 PUFA suppress T_H17 cell differentiation. n-3 PUFA directly modulate IL-6/gp130 signaling at the plasma membrane, thus decreasing T_H17 differentiation. A) n-3 PUFA decrease colocalization of gp130 in lipid rafts, as assessed by colocalization with cholera toxin (CTxB), a marker of lipid rafts. Red highlight indicates liquid ordered lipid rafts; Blue indicates bulk membrane. B) n-3 PUFA decrease the dimerization of gp130 upon IL-6 stimulation, suppressing downstream T_H17 differentiation (Allen et al., 2014).