How to reprogram microglia toward beneficial functions

Fumagalli, Marta; Lombardi, Marta; Gressèns, Pierre; Verderio, Claudia

doi:10.1002/glia.23484

Cited by 93 publications

(78 citation statements)

References 222 publications

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“…In one of our earlier proteome studies, we have shown that LPA affects the abundance of a number of metabolic enzymes involved in glycolysis [20]. Therefore pharmacological modulation of metabolic pathway utilization within the concept of immunometabolism [62] might offer novel and effective approaches to reprogram potentially neurotoxic microglia phenotypes [53].…”

Section: Discussionmentioning

confidence: 98%

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MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Plastira

Bernhart

Joshi

et al. 2020

J Neuroinflammation

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Background: In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia. Methods: In vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACSsorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia. Results: Under acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and-3, p65, and c-Jun) and secretion of IL-6 and TNFα. All three inhibitors decreased LPA-mediated secretion of IL-1β, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media.

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Section: Discussionmentioning

confidence: 98%

“…Several strategies to reprogram microglia towards a beneficial phenotype were proposed [53] and the ATX/ LPA/LPAR axis might offer new pharmacological opportunities for repolarization. Along the ATX/LPA/LPAR axis, several antagonists are in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Plastira

Bernhart

Joshi

et al. 2020

J Neuroinflammation

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“…Manipulating the microglial phenotype has therefore become a promising approach for therapeutic intervention in neurological diseases [16,17]. Because the metabolic program of immune cells is not only associated with, but also determinant for their phenotype, this constitutes a potential target.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming during Microglia Activation

et al. 2019

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Microglia, the specialized macrophages of the brain, can adopt different shapes and functions, some of which may be detrimental for nervous tissue. Similar to other immune cells, the metabolic program may determine the phenotypic features of microglia, and could constitute a therapeutic target in neurological diseases. Because the knowledge on microglial metabolism was sparse we here employed mouse primary microglia cells polarized into a pro- or anti-inflammatory state to define their metabolic features. After stimulation with either IL1β/IFNγ or IL4, the activity of glycolysis, glucose oxidation, glutamine oxidation, mitochondrial and peroxisomal fatty acid β-oxidation, and fatty acid synthesis, was assessed by using radiolabeled substrates. We complemented these data with transcriptome analysis of key enzymes orchestrating these metabolic pathways. Pro-inflammatory microglia exhibit increased glucose and glutamine metabolism and suppress both fatty acid oxidation and to a lesser extent fatty acid synthesis. On the other hand, anti-inflammatory microglia display changes only in fatty acid metabolism upregulating both fatty acid oxidation and fatty acid synthesis. Importantly, also human microglia-like cells differentiated from pluripotent stem cells upregulate glycolysis in pro-inflammatory conditions. Finally, we show that glycolytic enzymes are induced in a pro-inflammatory brain environment in vivo in mice. Taken together, the distinct metabolism in pro- and anti-inflammatory microglia can constitute a target to direct the microglial phenotype.

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“…Redirection of microglia from a detrimental to a regenerative phenotype is a major concept to develop new therapies targeting these cells [33]. Nitric oxide (NO), the product of iNOS activity, blunts mitochondrial respiration of pro-in ammatory macrophages and this dysfunction prevents editing macrophage towards an anti-in ammatory phenotype.…”

Section: Mdivi-1 Treatment Does Not Improve Microglial Repolarizationmentioning

confidence: 99%

Role of mitochondrial dynamics in microglial activation and metabolic switch

Montilla

Ruiz

Matute

et al. 2020

Preprint

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Background Microglia are the endogenous immune cells of the central nervous system (CNS) and act as sensors of injury in the brain, favouring its homeostasis. Their activation and polarization towards a pro-inflammatory phenotype are associated to injury and disease. These processes are linked to a metabolic reprogramming of the cells, characterized by high rates of glycolytic function and suppressed levels of oxidative phosphorylation. This metabolic switch can be reproduced in vitro by stimulation with lipopolysaccharide (LPS) plus Interferon-γ (IFNγ). In an attempt to understand the mechanisms regulating mitochondrial respiration abolishment, we examined potential alterations in mitochondrial features during the metabolic switch. In addition, we studied the possible implication of mitochondrial dynamics in the metabolic switch using the mitochondrial division inhibitor-1 (Mdivi-1), which blocks Drp1-dependent mitochondrial fission. Methods Cultured microglia was treated with LPS + IFNγ to reproduce the metabolic switch under pro-inflammatory stimuli in the absence or in the presence of Mdivi-1 to block mitochondrial fission. Mitochondrial membrane potential and mitochondrial calcium were measured with living cell imaging, and microglial polarization was assessed by immunofluorescence and qRT-PCR. The metabolic profile of the cells was measured using the Seahorse XFe96 Extracellular Flux Analyzer. Results Under conditions of mitochondrial respiration abolishment, microglia did not show any change in mitochondria morphology, nor in mitochondrial membrane potential, indicative of a limited impact in its viability. We provided evidence that reverse operation of F0F1-ATP synthase contributes to mitochondrial membrane potential. On the other hand. mitochondrial fission blockage significantly reduced the expression of pro-inflammatory markers in LPS + IFNγ-treated microglia, such as the inducible nitric oxide synthase (iNOS). However, this inhibition did not lead to a recovery of the oxidative phosphorylation ablation by LPS + IFNγ or to a microglia repolarization. Conclusions Altogether, these results suggest that Drp1-dependent mitochondrial fission, although potentially involved in microglial activation, does not play an essential role in metabolic reprogramming and repolarization of microglia.

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How to reprogram microglia toward beneficial functions

Cited by 93 publications

References 222 publications

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

MAPK signaling determines lysophosphatidic acid (LPA)-induced inflammation in microglia

Metabolic Reprogramming during Microglia Activation

Role of mitochondrial dynamics in microglial activation and metabolic switch

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