Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Plastira, I.
Effects of Lysophosphatidic Acid on Microglia Function
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 171
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- Autor*innen der Med Uni Graz:
- Plastira Ioanna
- Betreuer*innen:
- Heinemann Akos
- Marsche Gunther
- Sattler Wolfgang
- Altmetrics:
- Abstract:
- Microglia, the immunocompetent cells of the CNS, rapidly respond to brain injury and disease, alter their morphology, migrate towards the damaged tissue and play an important role in CNS regeneration. Extrinsic signals determine whether microglia acquire - depending on disease context - a beneficial or detrimental phenotype. Classically activated (M1) microglia synthesize pro inflammatory factors that inflict neuronal damage, while the production of trophic and anti-inflammatory factors by M2 microglia can support neuronal survival and regeneration. Under chronic inflammation, as observed in many neurodegenerative diseases, microglia are characterized by overactivation, dysfunction, secretion of pro inflammatory factors and neuronal toxicity. Their crucial role in brain homeostasis makes these cells potential therapeutic targets, which necessitate a thorough understanding of polarization cascades, and pathways that modulate their function. There is growing appreciation that the pathogenesis of many diseases is linked to dysregulated LPA signaling. LPA is a mixture of saturated or unsaturated acyl/alkyl residues esterified at the sn-1 or sn-2 position that are present in biological fluids including CSF. The majority of LPA is produced through autotaxin (ATX)-dependent cleavage of lysophosphatidylcholine and LPA signaling is mediated via six LPA receptors (LPAR1-6) that are all expressed in the brain. LPA has diverse biological functions mediated by downstream signaling through the different receptors. These receptors play prominent role in the central nervous system, and signaling is amplified at sites of inflammation where LPA concentrations are increased. The results of the present study provide evidence that LPA is a potent regulator of microglia biology and function. Increased LPA levels, as observed under inflammatory conditions, affected microglial morphology and promoted the migrational response. The LPA/LPAR5/PKD axis regulated the expression of migratory genes indicating possible downstream targets via which LPA signaling controls microglia chemotaxis. In addition, LPA promoted am M1-like phenotype in microglia. I observed elevated secretion of pro inflammatory mediators such as cytokines, chemokines, NO, and ROS, increased expression of M1 markers and microglia-mediated neurotoxicity. Pharmacological inhibition of the LPAR5/PKD/JNK axis significantly decreased the expression of these pro-inflammatory factors and abolished the LPA-induced activation of pro-inflammatory transcription factors, unraveling possible transcription programs that are involved in LPA-induced inflammatory response of microglia cells. The outcome of this study comprises of an important step towards a better understanding of LPA-mediated effects on the immune cells of the CNS. The results obtained during my PhD thesis should foster the study of LPA signaling and its impact on microglia function in the diseased brain. Interference with different members of the LPA signaling pathway, depending on the context of disease, may unravel possible new targets for modulating neuroinflammation that, until now, were not considered.