Neurosteroid allopregnanolone (3α,5α-THP) inhibits inflammatory signals induced by activated MyD88-dependent toll-like receptors

Abstract

We have shown that endogenous neurosteroids, including pregnenolone and 3α,5α-THP inhibit toll-like receptor 4 (TLR4) signal activation in mouse macrophages and the brain of alcohol-preferring (P) rat, which exhibits innate TLR4 signal activation. The current studies were designed to examine whether other activated TLR signals are similarly inhibited by 3α,5α-THP. We report that 3α,5α-THP inhibits selective agonist-mediated activation of TLR2 and TLR7, but not TLR3 signaling in the RAW246.7 macrophage cell line. The TLR4 and TLR7 signals are innately activated in the amygdala and NAc from P rat brains and inhibited by 3α,5α-THP. The TLR2 and TLR3 signals are not activated in P rat brain and they are not affected by 3α,5α-THP. Co-immunoprecipitation studies indicate that 3α,5α-THP inhibits the binding of MyD88 with TLR4 or TLR7 in P rat brain, but the levels of TLR4 co-precipitating with TRIF are not altered by 3α,5α-THP treatment. Collectively, the data indicate that 3α,5α-THP inhibits MyD88- but not TRIF-dependent TLR signal activation and the production of pro-inflammatory mediators through its ability to block TLR-MyD88 binding. These results have applicability to many conditions involving pro-inflammatory TLR activation of cytokines, chemokines, and interferons and support the use of 3α,5α-THP as a therapeutic for inflammatory disease.

Gut feelings: the microbiota-gut-brain axis on steroids

“…In addition to its influence on mood fluctuations, it demonstrates analgesic properties in neuropathic pain models, possibly through T-type calcium channels and GABA A receptor (184) (112). A recent study also reported its inhibitory activity on toll-like receptor 4 (TLR4), via MyD88-dependent signals that suppress neuroinflammation (17) (18). Pregnenolone sulfate, in contrast to allopregnanolone, inhibits GABA A receptor signaling by enhancing receptor desensitization (217).…”

Allopregnanolone: An overview on its synthesis and effects

“…Indeed, ALLO exerts a variety of protective effects in this process. For example, this neuroactive steroid reduces protein‐protein interactions initiating toll‐like receptor 4 (TLR4)‐dependent signalling in immune cells and the brain 261 alongside of TLR7 262 . In addition, its treatment decreases microglia reactivity and lymphocyte infiltration in an EAE experimental model, 149,236 as well as neuroinflammatory burden in AD models 237,238 .…”

PPAR-α Hypermethylation in the Hippocampus of Mice Exposed to Social Isolation Stress Is Associated with Enhanced Neuroinflammation and Aggressive Behavior

“…Thus, decreased hippocampus Allo levels in SI mice may play a role in the following: (1) the inflammatory processes resulting from PPAR-α downregulation and enhancement of NF-κB signaling, and (2) the behavioral dysfunction arising from the downregulation of Allo-modulated GABAergic neurotransmission. The mechanisms of stress-induced Allo biosynthesis downregulation in the contest of impaired NF-κB and TLR-4 pathways remain to be clarified, as well as whether TLR-4 abnormal activation occurring in stress-induced models of affective disorders [ 55 ] is linked to the downregulation of brain Allo levels. Indeed, exposure to TLRs agonists suppresses PPAR-α expression via a NF-κB-dependent signaling in astrocytes [ 56 ], raising the question of whether this can be an additional mechanism responsible for low Allo levels in pathophysiological conditions characterized by elevated inflammation and affective symptoms.…”