Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Joshi, L.
Effects of Lysophosphatidic Acid-mediated Signaling Cascades on
Microglia Inflammation and Metabolism
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medical University of Graz; 2021. pp.
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Holzer Peter
- Malli Roland
- Sattler Wolfgang
- Altmetrics:
- Abstract:
- Microglia are the resident immune cells of the CNS and contribute to brain development and homeostasis. They serve dual functions as glial cells and immune cells. They perform constant surveillance of the brain micro environment via a set of receptors termed as microglia sensome. Depending on the environmental stimuli, microglia adopt wide spectrum of activation state ranging from a pro-inflammatory to an anti-inflammatory phenotype. The polarization of microglia leads to changes in morphology, alterations in its phagocytic capacity, inflammasome activation, accompanied by the secretion of cytokines, chemokines and other inflammatory mediators. These responses are regulated through a combination of complex epigenetic, transcriptional, functional and metabolic changes that determine the neurotoxic or neuroprotective phenotype of microglia. One of the extrinsic signals which activate microglia is Lysophosphatidic acid (LPA). LPA is a bioactive lipid, which acts via G-protein coupled receptors (LPA1-6) to elicit a wide range of cellular responses. The major source of LPA is autotaxin (ATX)-dependent hydrolysis of lysophospholipids, primarily derived from membrane phospholipids. There is growing evidence suggesting that the pathogenesis of numerous diseases is linked to dysfunctional expression and activity of ATX, with subsequent changes in LPA signaling. The results of the present study demonstrated that systemic inflammation has a profound effect on neuroinflammation that involve the contribution of microglia activation. Pro-inflammatory stimuli such as LPS, initiates downstream signaling cascade to activate the ATX-LPA-LPAR axis to mediate inflammation in microglia. The inhibition of ATX (PF8380) and LPA5 (AS2717638) in endotoxemia showed promising effect in attenuating the neuroinflammatory response in LPS stimulated microglia in vitro (BV-2) and in an in vivo acute mouse model of sepsis. Hence, I provide proof that pharmacological intervention along the ATX-LPA-LPAR axis can be a potential strategy against neuroinflammation. Emerging studies indicate that metabolic reprograming acts as an underlying factor for the regulation of immune function of microglia. In the present study, I provide evidence that LPA mediates the inflammatory response of primary murine microglia via LPA5. In addition, this inflammatory response in microglia is accompanied by changes in the metabolic phenotype of the cells. LPA induces aerobic glycolysis, lipogenesis, and increased amino acid uptake in BV-2 microglia. Further, LPA increases the utilization of pentose phosphate pathway to generate NADPH, a reducing equivalent of the primary microglia. All of these metabolic alterations were mediated via LPA5 as supported by genetic deletion of the receptor. The outcomes of this study provide us with a better understanding of LPA-mediated effects in microglia. These results build a foundation for understanding neuroinflammation in a different light. Interfering with LPA signaling can be a possible target in modulating the inflammatory and metabolic profile of microglia, and hence contribute to develop targeted therapies for neurodegenerative diseases.