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. 2022 Oct 21;13:936167. doi: 10.3389/fimmu.2022.936167

Figure 2.

Figure 2

Schematic of the metabolic reprogramming of M1 macrophages following LPS (A) or silica (B) exposure. Upon LPS or silica activation, M1 macrophages show enhancement of aerobic glycolysis, glucose uptake, and conversion into lactate; increased flux through the PPP, NADPH generation, and production of fatty acids, NO, and ROS (wide red arrows). LPS induces two breakpoints in the Krebs cycle (IDH and SDH), leading to the mitochondrial accumulation of citrate and succinate. Accumulation of citrate increases the synthesis of itaconate, and citrate translocation into the cytosol, via mCIC, resulting in upregulation of synthesis of fatty acids, PGE2, NO, ROS, and transcription and secretion of TNF-α (wide red arrows). The dysfunction of SDH (Complex II of ETC), results in the accumulation of succinate, also due to the glutamine-dependent anaplerosis via the GABA shunt, and reversion of the electron transport (RET) toward complex I, which rises the generation of ROS, stabilization of HIF-1α, activation of the NLRP3 inflammasome and release of pro-inflammatory cytokine IL-1β. (LPS-specific activated pathways are represented with green arrows.) In contrast to LPS, silica also modulates the Krebs cycle, but the intracellular level of all key Krebs cycle intermediates, including succinate and citrate, and amino acids is measured below baseline, probably as a result of high demand and consumption (red arrows). In addition, the enhanced aerobic glycolysis occurs at the expense of mitochondrial respiration, which is sustained only by an upregulated complex II activity, while complex I is impaired, leading to the generation of an excessive amount of ROS. The latter in addition to the intrinsic toxicity of silica particles drive the stabilization of HIF-1α, activation of NRLP3 inflammasome, and release of IL-1β. Similar to LPS-activated macrophages, hyperproduction of malonyl-CoA is necessary for the synthesis of fatty acids, PGE2, NO, ROS, and transcription and secretion of TNF-α (wide red arrows). (Silica-specific activated pathways are represented with red arrows.).