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DOI: 10.1055/s-0034-1371978
Dehydroepiandrosterone and a synthetic analogue regulate microglial cell polarization
The decline of the most abundant circulating adrenal steroid hormone in humans, dehydroepiandrosterone (DHEA), produced by the adrenal cortex and the Central Nervous System (CNS), with advancing age, has been linked to the development of neurodegenerative diseases. Microglial cells, the CNS-resident macrophages, are prone to a macrophages-like polarization: in their resting state they appear in a ramified “M2” phenotype-like state, maintaining CNS tissue homeostasis, while upon activation, they acquire a pro-inflammatory “M1”-like phenotype. Recently we have identified DHEA as a novel ligand of the Nerve Growth Factor Tropomyosin Related kinase A (TrkA). Furthermore we have synthesized a DHEA analogue, called BNN27 that cannot be converted to androgen or estrogen, which also binds to and activates NGF receptors.
Here we show that DHEA and BNN27 dampen microglia-mediated inflammation after LPS stimulation, through a TrkA-mediated mechanism, while they up-regulate the expression of M2-related genes (Arg1, Ym1, Fizz1, IL-4) in microglial cells. NGF, the prototype ligand of TrkA, exerts similar anti-inflammatory effects in microglial cells. The anti-inflammatory effect of NGF and DHEA is PI3K/Akt pathway-dependent. The effect of DHEA and BNN27 is microglia-specific, as it is not observed in peritoneal or bone marrow-derived macrophages. These findings indicate a role of DHEA in the regulation of microglial cell polarization, and thus potentially the development and progression of neuro-inflammatory diseases, while the anti-inflammatory effects of the non-metabolizable BNN27 potentially suggest new options in the treatment of CNS inflammation.