Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release

Abstract

We turnover billions of apoptotic cells daily, and these are removed by professional and non-professional phagocytes via efferocytosis 1 . Characterizing the transcriptional program of phagocytes, we discovered a novel solute carrier family (SLC) gene signature (involving 33 SLC members) that is specifically modified during efferocytosis, but not antibody-mediated phagocytosis. Assessing the functional relevance of these SLCs, we noted a robust induction of an aerobic glycolysis program in efferocytic phagocytes, initiated by SLC2A1-mediated glucose uptake, with concurrent suppression of oxidative phosphorylation program. Interestingly, the different steps of phagocytosis 2 , i.e. smell (‘find-me’ signals/ sensing factors released by apoptotic cells), taste (phagocyte-apoptotic cell contact), and ingestion (corpse internalization), activated different SLCs and other molecules to promote glycolysis. Further, lactate, a natural by-product of aerobic glycolysis 3 , was released via another SLC (SLC16A1) that was upregulated after corpse uptake. While glycolysis within phagocytes contributed to actin polymerization and the continued uptake of corpses, the lactate released via SLC16A1 influenced the establishment of an anti-inflammatory tissue environment. Collectively, these data reveal a novel SLC program activated during efferocytosis, identify a previously unknown reliance on aerobic glycolysis during apoptotic cell uptake, and that glycolytic byproducts of efferocytosis can also influence other cells in the microenvironment.

Epidemiological and clinical features of COVID-19 patients with and without pneumonia in Beijing, China

“…Major symptoms at illness onset were fever (85.5%), cough (50.9%), fatigue (27.3%), myalgia (20.0%), and sputum production (20.0%). Of the 55 patients, 26 (47.3%) had at least 1 coexisting health conditions. Hypertension (11 [20.0%]) and diabetes (6 [10.9%]) were the most common ones.…”

“…Efferocytosis can promote glucose uptake and lactate release. 26 patients with and without pneumonia were evaluated during hospital stay. Neutrophil proportion and NLRs were higher in pneumonia patients than in pneumonia-free patients, indicating systemic inflammation is apparent.…”

Microglial Corpse Clearance: Lessons From Macrophages

“…Phagocytosis-induced metabolic adaptations are less known. In macrophages, phagocytosis of apoptotic cells drives a downregulation of fatty acid oxidation and de novo cholesterol, while promoting a metabolic shift that upregulates glycolisis and reduces oxidative phosphorylation (91,106). In fact, phagocytosis triggers mitochondrial adaptations, such as mitochondrial fission (106) and decreased mitochondrial membrane potential via mitochondrial uncoupling protein 2 (UCP2) (107), which together with increased glycolisis (91) ensure the continued uptake of corpses.…”

“…In fact, phagocytosis triggers mitochondrial adaptations, such as mitochondrial fission (106) and decreased mitochondrial membrane potential via mitochondrial uncoupling protein 2 (UCP2) (107), which together with increased glycolisis (91) ensure the continued uptake of corpses. In addition, increased lactate release promotes the establishment of an anti-inflammatory environment (91). However, phagocytosis-induced metabolic adaptations not only have an effect during phagocytosis, but also trigger longlasting effects.…”

Immunometabolism of pro-repair cells

“…Lactate, a frequently measured metabolite in the clinical setting, accumulates in damaged and hypoxic tissues. Efferocytosis of apoptotic cells activates an aerobic glycolysis program that leads to release of lactate into the extracellular environment (115). Extracellular lactate inhibits motility of murine and human CD4 + and CD8 + T cells (116).…”