Regulation of microglia-mediated neuroinflammation by microneurotrophins
Public Health, Healthcare Research, Social and Occupational Medicine
Final Report Abstract
Chronic neuroinflammation is a feature of many neurodegenerative diseases. Microglia, the resident immune cells of the brain, are key players in neuroinflammation and, if chronically activated, they can drive neurodegeneration. The brain is a highly steroidogenic organ, synthesizing or metabolizing the so called, neurosteroids. Neurosteroid synthesis can be substantially affected by neuroinflammation, while, in turn, several neurosteroids might regulate neuroinflammatory responses. Here we have studied the role of dehydroepiandroterone (DHEA), an abundant neurosteroid, in microglia-mediated neuroinflammation. We showed that DHEA exerts anti-inflammatory effects in vitro, in cultured primary microglia, and in vivo in lipopolysaccharide (LPS)-induced acute brain inflammation. The antiinflammatory effect of DHEA was evidenced by down-regulation of inflammatory cytokines, chemokines and inducible nitric oxide synthase (iNOS). Moreover, we revealed that the Akt1/Akt2 – CREB – Jmjd3 pathway mediates the anti-inflammatory effect of DHEA in microglia and is activated by the Nerve Growth Factor (NGF) receptor, Tropomyosin related kinase A (TrkA). DHEA was previously shown to bind and activate the TrkA receptor in neuronal cells, mimicking some neuroprotective effects of NGF. Due to its small molecular size we therefore termed it a ‘microneurotrophin’. Having identified TrkA as a regulator of microglial inflammatory responses, we also assessed the role of its prototype ligand, NGF, in microglia-mediated neuroinflammation. We showed, that NGF also exerts anti-inflammatory effects in microglia but not in peripheral macrophages. NGF mediates its antiinflammatory effects in at least two ways: by acute regulation of the pro-inflammatory signaling pathways NFκB and JNK, and through regulation of glycolysis. The latter is strongly induced in inflammatory microglia and mediates expression of inflammatory genes, such as IL6 and IL1β. Glucose uptake and expression of the glycolytic genes Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (Pfkfb3) and Lactate dehydrogenase A (Ldhα) were reduced by NGF in LPS-stimulated microglia. Although our studies indicate an inflammation – limiting and neuroprotective effect of NGF in the central nervous system (CNS), NGF has a poor therapeutic potential due to its inability to transpass the blood brain barrier (BBB) thereby excluding its peripheral administration. On the other hand, DHEA mimicking some of the effects of NGF, can reach the brain when systemically applied. However, due to its metabolism to androgens and estrogens its use could associate with an increased risk of hormonedependent cancer development. Therefore, DHEA analogues with a reduced ability to be metabolized to androgens and estrogens were synthesized, one of which, called BNN27, was found to have antiinflammatory functions in microglia. More synthetic and natural compounds selected through screenings of small-molecule libraries are currently tested. Concluding, through this study we have shown that DHEA and NGF can regulate microglia-mediated inflammation and revealed implicated molecular mechanisms. These findings could be therapeutically harnessed in the treatment of neuroinflammation in the context of neurodegenerative diseases.
Publications
- S100A9 induces monocyte/ macrophage migration via EMMPRIN. Thromb Haemost. 2017 Feb 28;117(3):636-639
Alexaki VI, May AE, Fujii C, V Ungern-Sternberg SN, Mund C, Gawaz M, Chavakis T, Seizer P
(See online at https://doi.org/10.1160/TH16-06-0434) - DHEA inhibits acute microglia-mediated inflammation through activation of the TrkA-Akt1/2-CREB- Jmjd3 pathway. Mol Psychiatry. 2018 Jun;23(6):1410-1420
Alexaki VI, Fodelianaki G, Neuwirth A, Mund C, Kourgiantaki A, Ieronimaki E, Lyroni K, Troullinaki M, Fujii C, Kanczkowski W, Ziogas A, Peitzsch M, Grossklaus S, Sönnichsen B, Gravanis A, Bornstein SR, Charalampopoulos I, Tsatsanis C, Chavakis T
(See online at https://doi.org/10.1038/mp.2017.167) - Nerve Growth Factor modulates LPS - induced microglial glycolysis and inflammatory responses. Exp Cell Res. 2019 Apr 15;377(1-2):10-16
Fodelianaki G, Lansing F, Bhattarai P, Troullinaki M, Zeballos MA, Charalampopoulos I, Gravanis A, Mirtschink P, Chavakis T, Alexaki VI
(See online at https://doi.org/10.1016/j.yexcr.2019.02.023) - Nerve growth factor regulates endothelial cell survival and pathological retinal angiogenesis. J Cell Mol Med. 2019 Jan 24
Troullinaki M, Alexaki VI, Mitroulis I, Witt A, Klotzsche-von Ameln A, Chung KJ, Chavakis T, Economopoulou M
(See online at https://doi.org/10.1111/jcmm.14002)
