Fatty acid oxidation in immune function

Abstract

Cellular metabolism is a crucial determinant of immune cell fate and function. Extensive studies have demonstrated that metabolic decisions influence immune cell activation, differentiation, and cellular capacity, in the process impacting an organism's ability to stave off infection or recover from injury. Conversely, metabolic dysregulation can contribute to the severity of multiple disease conditions including autoimmunity, alloimmunity, and cancer. Emerging data also demonstrate that metabolic cues and profiles can influence the success or failure of adoptive cellular therapies. Importantly, immunometabolism is not one size fits all; and different immune cell types, and even subdivisions within distinct cell populations utilize different metabolic pathways to optimize function. Metabolic preference can also change depending on the microenvironment in which cells are activated. For this reason, understanding the metabolic requirements of different subsets of immune cells is critical to therapeutically modulating different disease states or maximizing cellular function for downstream applications. Fatty acid oxidation (FAO), in particular, plays multiple roles in immune cells, providing both pro- and anti-inflammatory effects. Herein, we review the major metabolic pathways available to immune cells, then focus more closely on the role of FAO in different immune cell subsets. Understanding how and why FAO is utilized by different immune cells will allow for the design of optimal therapeutic interventions targeting this pathway.

Keywords: adoptive cellular therapies; fatty acid oxidation (FAO); immune cell differentiation; immunometabolism; metabolic adaptation; metabolic dysregulation.

Figure 1

Intracellular transportation and oxidation of long-chain fatty acids. Long-chain fatty acids (LCFAs) are transported inside the cell via specialized transporters, where they are acted upon by a family of acyl-CoA synthetase enzymes to generate long-chain acyl-CoA (LC-Acyl-CoA) moieties. LC-Acyl-CoA is then conjugated to free carnitine by the enzyme carnitine-palmitoyltransferase 1a (CPT1a), in a conjugation reaction often delineated as the rate-limiting step in fatty acid oxidation. This conjugation reaction generates LC-acylcarnitine species, which can then be transported into the mitochondria by the carnitine-acylcarnitine translocase protein (CACT). Once inside the mitochondria, LC-acylcarnitine is deconjugated by the enzyme carnitine palmitoyltransferase 2 (CPT2) to free the LC-Acyl-CoA and carnitine, the latter of which is transported back out of the mitochondria in a loop known as the carnitine shuttle. Once inside the mitochondria, LC-Acyl-CoA enters into the beta-oxidation spiral, which is a 4-step series of dehydrogenation, hydration, oxidation, and finally thiolysis. Every cycle produces one molecule each of acetyl-CoA, NADH, and FADH2 while shortening the parent LC-Acyl-CoA by 2 carbons. This spiral continues until the LCFA is entirely broken down. The reducing agents, NADH and FADH2, produced during the β-oxidation reaction are used to fuel the electron transport chain, while the acetyl-CoA can either enter the tricarboxylic acid cycle as an intermediate or be used for ketogenesis. LCEH, long-chain enoyl-CoA hydratase; LCHAD, long-chain hydroxyl acyl-CoA dehydrogenase; LCKAT, long-chain 3-keto-acyl CoA thiolase, and VLCAD, very long-chain acyl-CoA dehydrogenase. Figure created using BioRender.