Abstract
Microglial activation by oleate and palmitate differentially modulates brain inflammatory status. However, the metabolic reprogramming supporting these reactive phenotypes remains unknown. Employing real-time metabolic measurements and lipidomic analysis, we show that both fatty acids promote microglial oxidative metabolism, while lipopolysaccharide (LPS) enhances glycolytic rates. Interestingly, oleate treatment was followed by enrichment in storage lipids bound to polyunsaturated fatty acids (PUFA), in parallel with protection against oxidative imbalance. Palmitate, in turn, induced a distinct lipid distribution defined by PUFA linked to membrane phospholipids, which are more susceptible to lipid peroxidation and inflammatory signaling cascades. This distribution was mirrored by LPS treatment, which led to a strong pro-inflammatory phenotype in microglia. Thus, although both oleate and palmitate preserve mitochondrial function, a contrasting lipid distribution supports differences in fatty acid-induced neuroinflammation. These data reinforce the concept that reactive microglial profiles are achieved by stimulus-evoked remodeling in cell metabolism.
Highlights
Microglia are resident macrophages of the central nervous system (CNS), presenting multiple roles on the maintenance of brain homeostasis [1]
LPS treatment resulted in changes in microglial mitochondrial respiration under basal conditions (Figure 1A,C), or the respiratory rates obtained in the absence of any mitochondrial modulators subtracted from non-mitochondrial respiration, as indicated by ‘1’ in explanatory Figure 1B
Microglial activation has often been studied as a bimodal process, with focus on the interplay between extreme pro-inflammatory or anti-inflammatory profiles such as those induced by LPS and IL-4, respectively [1]
Summary
Microglia are resident macrophages of the central nervous system (CNS), presenting multiple roles on the maintenance of brain homeostasis [1]. These cells are phenotypically flexible and control several process in CNS development and physiology, such as synaptic maturation and plasticity [2]. Once exposed to pathological signals, microglia are activated to more reactive states that are supported by defined molecular and morphological remodeling [3]. Mechanisms controlling different microglial reactive states are not yet fully understood. Anti-inflammatory activation such as that induced by interleukin-4 (IL-4) is more flexible and can be sustained by different metabolic pathways [7,8]. Microglial metabolism in overt activation has been detailed, the metabolic reprogramming supporting intermediate microglial reactive states is not known
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