Fa(c)t checking: How fatty acids shape metabolism and function of macrophages and dendritic cells

Abstract

In recent years there have been major advances in our understanding of the role of free fatty acids (FAs) and their metabolism in shaping the functional properties of macrophages and DCs. This review presents the most recent insights into how cell intrinsic FA metabolism controls DC and macrophage function, as well as the current evidence of the importance of various exogenous FAs (such as polyunsaturated FAs and their oxidation products-prostaglandins, leukotrienes, and proresolving lipid mediators) in affecting DC and macrophage biology, by modulating their metabolic properties. Finally, we explore whether targeted modulation of FA metabolism of myeloid cells to steer their function could hold promise in therapeutic settings.

Keywords: Dendritic cells; Fatty Acids; Macrophages; Metabolism; Proresolving mediators.

Figure 1

Cellular metabolism of intra‐ and extracellular fatty acids. A schematic overview of key processes involved in cellular FA uptake and metabolism. Core metabolic pathways connected to FA metabolism are indicated as well as the main processes involved in SPM synthesis from PUFAs such as ω‐3 and ω‐6 FAs. Specifically, PUFAs, many of which are essential FAs obtained from food, can be metabolized by cyclooxygenases (COX) and lipoxygenases (LOX) to give rise to SPMs. Main PUFAs that serve as substrate for these enzymes are linoleic acid (LA) and arachidonic acid (AA), which are ω‐6 PUFAs, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both ω‐3 PUFAs. Several enzymatic reactions lead to synthesis of SPMs (highlighted in green). The metabolism of EPA by COX‐2 eventually gives rise to E‐series Resolvins (RvE), while with DHA the products are more diverse. The actions of LOX on DHA lead to products from the Maresin (MaR) family, while both LOX and COX‐2 can give products from the Protectin family (PD) or D‐series Resolvins (RvD). In the case of ω‐6 PUFAs, such as AA, COX and LOX, give products.

Figure 2

FA metabolism of pro‐ and anti‐inflammatory macrophage Schematic depiction of how FA metabolism and uptake control the function of (A) pro‐ and (B) anti‐inflammatory macrophages. Green lines indicate positive signaling, while red lines indicate an inhibitory effect. (A) Proinflammatory macrophages increase FA synthesis upon TLR signaling. This increase in FA synthesis drives 4‐1BBL activity which helps to sustain inflammation. TLR‐driven FA synthesis also leads to an increase in lipid droplets which is associated with increased PGE2 and IL‐1β synthesis. Moreover, TLR signaling induces iNOS expression and subsequent NO synthesis which inhibits the ETC, thereby reducing FAO, and promoting ROS formation which helps with microbicidal functions. Increased FA synthesis upon TLR stimulation also leads to SFA synthesis, which increases PC levels in the cell membrane, leading to less fluidity and K⁺ efflux, thereby activating NLPR3 and IL‐1β synthesis. TLR1/2, TLR7, and TLR9 activation increased FA synthesis and de novo SFA and MUFA synthesis. TLR3 activation leads to the opposite effect, inhibiting FA synthesis, along with MUFA and SFA synthesis. (B) IL‐4R signaling activates STAT1, STAT3, and STAT6 which promote the transcription of TAM genes and CD36. IL‐4R signaling also promotes de novo FA synthesis which increases Acyl‐CoA levels in the cell. Extrinsic FAs can also increase Acyl‐CoA levels by being transported intracellularly by CD36 or FATP‐1. Increased Acyl‐CoA promotes OXPHOS and FAO in a CPT1a‐dependent manner. The increased flux in OXPHOS and FAO results in elevated levels of mitochondrial Acetyl‐CoA which can be transported to the cytosol in an ACLY‐dependent manner or through the Malate‐Aspartate shuttle. Cytosolic Acetyl‐CoA can participate in histone acetylation of M2‐like and TAM genes. PGE2 impairs mitochondrial membrane potential in M2‐like macrophages by dysregulation of the Malate‐Aspartate shuttle by increasing cAMP‐induced Got1 expression.

Figure 3

FA metabolism of immunostimulatory and tolerogenic DCs: Schematic depiction of how FA metabolism and uptake control the function of (A) immunostimulatory and (B) tolerogenic dendritic cells. Green lines indicate positive signaling, while red lines indicate an inhibitory effect. Dashed lines represent effects from exogenous stimuli. (A) In immunostimulatory DCs, TLR signaling increases FA synthesis to promote ER expansion and LD formation, which contributes to upregulation of MHCII and MHCI. PGC1α and PPARγ activation is also associated with increased FA synthesis in immunostimulatory DCs. TLR7/8 stimulation can lead to the phosphorylation of BCKDE1α in a PINK‐mediated manner. This results in increased OXPHOS and FAO which in turn is associated with increased activation of cDCs and pDCs. Additionally, extrinsic FAs, such as OA and PA, which are transported intracellularly by MSR1, can boost TLR4 signaling and increase IL‐23 synthesis. (B) In tolerogenic DCs, increased OXPHOS and FAO are associated with reduced IL‐6 and IL‐12 synthesis and increased IDO expression. Tumor‐derived FAs can increase OXPHOS and FAO by either being transported by CPT1a or by activating PPARα. This PPARα activation can also increase LD formation, which have a high content of oxidized PUFAs. Extrinsic FAs transported by MSR1 and FABP4 can feed these LDs and increase their oxidized PUFA content. These LDs, and tumor‐derived FAs themselves, impair cross‐presentation by suppressing MHCI surface expression. External stimuli, such as VitD3 and Wnt5a, can also increase FAO and OXPHOS, with Wnt5a doing so in a PPARγ‐dependent manner.