Anti-inflammatory effects of minocycline are mediated by retinoid signaling




Minocycline is a lipophilic tetracycline of increasing appeal in neuroscience as it inhibits microglial activation, a mechanism involved in numerous neuropsychiatric disorders. Own data point towards retinoid-mediated effects of minocycline in murine brain and skin, and towards a vicious cycle of neuroinflammation which is driven by microglial activation-induced breakdown of local retinoids such as retinoic acid (RA). We therefore sought to study minocycline’s anti-inflammatory effects on human microglial-like monocyte-derived cells in the context of retinoid signaling.


As hypothesized, minocycline exposure resulted in a substantial increase of RA levels in the human monocytic cell line THP-1. While pro-inflammatory stimulation with lipopolysaccharides resulted in increased tryptophane-degrading indoleamine-2,3-dioxygenase IDO-expression and TNF-α levels in primary human monocyte-derived microglial-like cells, this effect was attenuated by minocycline only in the presence of retinoids. The anti-inflammatory effects of minocycline on TNF-α expression were completely abolished by a pharmacological blockage of retinoic acid receptors (RARs) using BMS-493 and unaffected by selectively blocking retinoid-X-receptors using UVI-3003.


Our data indicate for the first time a RA-dependent, anti-inflammatory effect for minocycline in human microglial-like cells via inhibition of local RA turnover. The RA-dependent mode of action for minocycline appears to be predominantly mediated through RAR-signaling.

© The Author(s) Vera Clemens, Francesca Regen, Nathalie Le Bret, Isabella Heuser and Julian Hellmann-Regen


Minocycline is a well-established lipophilic tetracycline and has recently gained much attention in the neuroscience context due to its potent ability to block microglial activation [1, 2, 3, 4, 5, 6], a mechanism involved in numerous neuropsychiatric disorders [7] including major depressive disorder [8, 9], schizophrenia [10], autism [11, 12] and Alzheimer’s Disease [13, 14].