Metabolic reprogramming in efferocytosis

Abstract

Efferocytosis refers to the process by which phagocytes specifically identify and eliminate apoptotic cells. This process is essential for both maintaining tissue homeostasis and suppressing inflammatory responses, as well as facilitating tissue repair. When phagocytes internalize apoptotic cells, which act as "nutrient packages," they undergo significant metabolic reprogramming. This reprogramming not only supplies energy and biosynthetic precursors necessary for engulfment but also critically influences the functional phenotype of phagocytes through complex molecular networks. These networks ultimately determine whether phagocytes adopt an anti-inflammatory resolution or a pathological pro-inflammatory state. This article offers a comprehensive analysis of the molecular regulatory mechanisms that underpin metabolic reprogramming during efferocytosis, aiming to elucidate the intricate regulatory networks formed by the interaction of metabolites as signaling molecules and classical signaling pathways. We examine how the three primary metabolic pathways-glucose, lipid, and amino acid metabolisms-are regulated by signals from efferocytosis and, in turn, modulate phagocyte function. A deeper understanding of the interplay between metabolic reprogramming and efferocytosis will provide a theoretical foundation and novel targets for treating diseases associated with impaired clearance of apoptotic cells.

Keywords: apoptotic cell clearance; efferocytosis; fatty acid oxidation; glycolysis; macrophages; metabolic reprogramming.

FIGURE 1

Lipid mediators such as lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), and sphingosine-1-phosphate (S1P) function as “find me” signals, whereas phosphatidylserine (PS) serves as an “eat me” signal, facilitating signal communication pathways essential for the initiation and progression of efferocytosis. S1P is also capable of activating the erythropoietin (EPO) signaling pathway, thereby influencing the peroxisome proliferator-activated receptor gamma (PPARγ) to upregulate Mer tyrosine kinase (MerTK) and caspase-6 (Cas6), which are molecules associated with efferocytosis. 2. Fatty acid oxidation (FAO) mediated by carnitine palmitoyltransferase 1a (CPT1a) provides energy necessary for the formation of efferocytic phagosomes and cytoskeletal rearrangement, and is critical for the activation of interleukin-4 (IL-4)-mediated M2 macrophages. 3. Macrophages sustain effective localization of PS receptors by storing or exporting cholesterol or cholesteryl esters derived from apoptotic cells. Concurrently, cholesterol can activate nuclear cholesterol receptors liver X receptor alpha (LXRα), PPARγ, and PPAR delta (PPARδ) to upregulate the expression of anti-inflammatory factors interleukin-10 (IL-10) and transforming growth factor beta (TGFβ), as well as the phagocytic receptor MerTK, thereby maintaining the stability of efferocytosis. 4. Phagocytes can absorb lipids through their surface lipid sensor, triggering receptor expressed on myeloid cells 2 (Trem2), and influence efferocytosis by regulating lipid metabolism. 5. Efferocytosis can modulate the production of the anti-inflammatory factor IL-10 and, through activation of the MerTK receptor, stimulate 5-lipoxygenase (5-LOX). In conjunction with 12/15-lipoxygenase (12/15-LOX), this catalyzes the production of specialized pro-resolving mediators (SPMs), which in turn promote efferocytosis. This interaction ultimately facilitates the resolution of inflammation.

FIGURE 2

(A) Macrophages: During aerobic glycolysis, the uptake and utilization of glucose, mediated by SLC2A1, facilitate actin polymerization during phagocytosis. Concurrently, lactate release mediated by SLC16A1 promotes the polarization of immature macrophages and the release of anti-inflammatory factors, thereby aiding in the clearance of apoptotic cells. The phagocytosis of apoptotic cells by macrophages stimulates Akt dephosphorylation, leading to the phosphorylation and subsequent degradation of TXNIP. This process releases the glucose transporter GLUT1, increasing glucose uptake and thereby enhancing glycolysis. Akt-mediated phosphorylation of PFKFB2 catalyzes the production of Fru-2,6-P2, which activates phosphofructokinase-1 (PFK-1), further promoting glycolysis. Lactate produced during glycolysis can increase the surface expression of phagocytic receptors MerTK and LRP1 in a calcium-dependent manner, thereby facilitating the sustained uptake of apoptotic cells. MCTRs can promote macrophage phagocytosis by regulating Rac1 activity and upregulating glycolysis. Dicer inhibits the phagocytic function of macrophages and their inflammatory response during the clearance of apoptotic cells by suppressing the expression of PPP-related genes. Under chronic physiological hypoxia, macrophages can effectively shunt glucose into the PPP, and the NADPH generated by the PPP can protect macrophages from excessive lysosomal acidification and oxidative stress, thereby enhancing their efferocytosis and improving cellular adaptability to maintain critical homeostatic functions. (B) Dendritic Cells: SLC7A11 inhibits the phagocytosis of apoptotic cells by dendritic cells by suppressing the conversion of glycogen stored in DCs into glucose and the subsequent process of aerobic glycolysis.

FIGURE 3

The metabolic products of amino acids, resulting from the degradation of apoptotic cells by macrophages, play a crucial role in regulating the resolution of inflammation and the efficiency of subsequent phagocytosis. This regulation occurs through the modulation of signal transduction processes, energy metabolism, and the transcription of anti-inflammatory and pro-repair genes within macrophages. Rac1 is instrumental in cytoskeletal remodeling by affecting the stability of Dbl mRNA, which encodes a GTP exchange factor. This factor activates the Rac1 protein, thereby stimulating cytoskeletal rearrangement in macrophages to enhance their efficiency in continuous phagocytosis. The tryptophan metabolite kynurenine (Kyn) can bind to the downstream aryl hydrocarbon receptor (AhR), influencing signal transduction processes in macrophages and promoting the expression of anti-inflammatory and pro-repair genes, such as Il-4 and Tgfb1, thereby facilitating tissue repair. The methionine metabolite S-adenosylmethionine (SAM) undergoes epigenetic modification catalyzed by the methyltransferase DNMT3A, activating the downstream PGE2-TGFβ1 pathway and regulating the expression of anti-inflammatory and pro-repair genes. Elevated intracellular glutamine concentrations in macrophages are converted through a non-canonical transaminase pathway that integrates oxidative stress buffering with ATP production, thus meeting the high-energy demands of actin dynamics and cytoskeletal rearrangement.