Role of lipids in the metabolism and activation of immune cells

Abstract

Immune cell plasticity has extensive implications in the pathogenesis and resolution of metabolic disorders, cancers, autoimmune diseases and chronic inflammatory disorders. Over the past decade, nutritional status has been discovered to influence the immune response. In metabolic disorders such as obesity, immune cells interact with various classes of lipids, which are capable of controlling the plasticity of macrophages and T lymphocytes. The purpose of this review is to discuss lipids and their impact on innate and adaptive immune responses, focusing on two areas: (1) the impact of altering lipid metabolism on immune cell activation, differentiation and function and (2) the mechanism by which lipids such as cholesterol and fatty acids regulate immune cell plasticity.

Keywords: Fatty acids; Inflammation; Macrophages; Oxysterols; T lymphocytes.

Fig. 1. Immune cell phenotypes in adipose tissue, arteries and liver during metabolic disease

In lean adipose tissue, CD4⁺ lymphocytes and M2 macrophages express an antiinflammatory phenotype. During conditions of overnutrition or obesity, lipid mediators (SFA) are elevated and regulate the influx and activation of inflammatory macrophages (M1) and lymphocytes (Th1, CTL and Th17) in adipose tissue. In CVD, both M1 and M2 macrophages are present. In the arteries, macrophages infiltrate the arteries and engulf oxidized cholesterol, converting macrophages into foam cells. Similar to adipose tissue, the liver consists of antiinflammatory immune cells such as M2 associated Kupffer cells and CD4⁺ lymphocytes (Th2 and Treg). In fatty liver disease, lipid levels are increased and lead to the recruitment of inflammatory monocytes (Ly6C^hi) that differentiate into M1 macrophages. Likewise, inflammatory Th1, CTL, and Th17 cells infiltrate the liver.

Fig. 2. SREBP activation is linked to a proinflammatory phenotype in macrophages

SFAs and LPS activate NFκB through TLR4-dependent and TLR4-independent pathways. Oxysterols (27HC) activate NFκB through estrogen-receptor-mediated signaling pathways. Activation of NFκB induces expression of inflammatory genes, driving the M1 phenotype. However, activation of NFκB also induces the expression of SREBP, promoting lipid synthesis and accumulation. SREBP regulates ACC expression, which drives cholesterol synthesis via the production of malonyl CoA.

Fig. 3. Up-regulation of LXR and β-oxidation drives an antiinflammatory phenotype in macrophages

In macrophages, two lipid mediated pathways drive the antiinflammatory phenotype. (1) Cholesterol is taken by macrophages through the CD36 receptor. Cholesterol is converted into oxysterols by the enzyme CYP27A1. Oxysterols bind to LXR, leading to lipid efflux and cholesterol transport. Activation of LXR dampens inflammation by inhibiting the activity of NFκB. (2) AMP levels are elevated through metabolic factors such as adiponectin or starvation, leading to the activation of AMPK. AMPK inactivates ACC, leading to the reduction of malonyl CoA. Reduced malonyl CoA production increases CPT1 activity in mitochondria driving fatty acid oxidation.