n-3 Polyunsaturated fatty acids exert immunomodulatory effects on lymphocytes by targeting plasma membrane molecular organization

Abstract

Fish oil, enriched in bioactive n-3 polyunsaturated fatty acids (PUFA), has therapeutic value for the treatment of inflammation-associated disorders. The effects of n-3 PUFAs are pleiotropic and complex; hence, an understanding of their cellular targets and molecular mechanisms of action remains incomplete. Here we focus on recent data indicating n-3 PUFAs exert immunosuppressive effects on the function of effector and regulatory CD4(+) T cells. In addition, we also present emerging evidence that n-3 PUFAs have immunomodulatory effects on B cells. We then focus on one multifaceted mechanism of n-3 PUFAs, which is the alteration of the biophysical and biochemical organization of the plasma membrane. This mechanism is central for downstream signaling, eicosanoid production, transcriptional regulation and cytokine secretion. We highlight recent work demonstrating n-3 PUFA acyl chains in the plasma membrane target the lateral organization of membrane signaling assemblies (i.e. lipid rafts or signaling networks) and de novo phospholipid biosynthesis. We conclude by proposing new functional and mechanistic questions in this area of research that will aid in the development of fish oil as adjuvant therapy for treating unresolved chronic inflammation.

Figure 1. n-3 PUFAs disrupt cholera toxin induced clustering of GM1 molecules on the outer leaflet of the B cell plasma membrane

(A) Sample images of naïve B220⁺ B cells isolated from a C57BL/6 mouse fed a control diet (CD) or a diet enriched in a high dose of n-3 PUFAs. (B) Quantification of cholera toxin induced clusters. Data are from a recent study on n-3 PUFAs and rafts by the Shaikh lab (Rockett et al., 2011).

Figure 2. n-3 PUFAs increase lipid raft molecular order and suppress the recruitment and activation status of signaling proteins in the CD4⁺ T cell synapse

T cell activation results in an increase in lipid raft molecular order following the formation of the T cell – antigen presenting cell dependent immunological synapse. Green circles indicate cholesterol-enriched liquid ordered domains, which stabilize at the immunological synapse. Red circles indicate n-3 PUFA-dependent suppression of lipid second messengers (PIP₂, DAG) and proteins (PLCγ-1, PKCθ, F-actin, NF-kB) required for T cell activation. APC, antigen presenting cell.