The antidepressant effects of GM-CSF are mediated by the reduction of TLR4/NF-ĸB-induced IDO expression

Abstract

Background Indoleamine 2, 3-dioxygenase 1 (IDO) is responsible for the progression of the kynurenine pathway. This pathway has been implicated in the pathophysiology of inflammation-induced depression in which conventional antidepressants are not effective. It has been reported that granulocyte-macrophage stimulating factor (GM-CSF) could interfere with the induction of IDO in septic patients. We hypothesized that GM-CSF could exert antidepressant effects through IDO downregulation in a model for acute inflammation-induced depression. Methods To produce the model, lipopolysaccharide (LPS) (0.83 mg/kg) was administered intraperitoneally to mice. It has been well documented that LPS mediates IDO overexpression through TLR4/NF-ĸB signaling. In the treatment group, mice received GM-CSF (30 μg/kg, i.p.) thirty minutes prior to LPS injection. A validated selective serotonin reuptake inhibitor, fluoxetine (30 mg/kg i.p.), was also administered to an experimental group 30 min prior to LPS. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. To confirm that GM-CSF interferes with IDO induction in LPS treated mice, real-time PCR was used to quantify IDO mRNA expression. Furthermore, in order to study whether GM-CSF inhibits the TLR4/NF-ĸB signaling pathway, we measured levels ofpNF-ĸB and TLR4 by western blotting. Results GM-CSF demonstrated significant antidepressant activity in the presence of LPS on immobility ( p < .001) and latency ( p = .010) times in the forced swim test. In contrast, fluoxetine did not show any antidepressant activity on either immobility ( p = .918) or latency ( p = .566) times. Furthermore, GM-CSF inhibited the increase in IDO mRNA ( p = .032) and protein ( p = .016) expression as a result of LPS administration. A similar trend was observed for TLR4 ( p = .042) and pNF-ĸB ( p = .026) expression as both proteins showed reduced expression levels in the GM-CSF-pretreated group compared to the untreated (LPS) group. Conclusion Our results propose a promising antidepressant effect for GM-CSF possibly through the downregulation of IDO expression. This remedying effect of GM-CSF could be attributed to decreased amounts of TLR4 and active NF-ĸB in the treated mice.

Trained Innate Immunity by Repeated Low-Dose Lipopolysaccharide Injections Displays Long-Term Neuroprotective Effects

“…Our results are in line with recent studies indicating that LPS preconditioning blunt microglia proinflammatory response by epigenetic suppression of IL-1 β , TNF- α , and IL-6 gene, as well as shifting the proinflammatory response to the anti-inflammatory reaction and increase in the phagocytic activity [ 23 ]. The mechanism might be related to NF- κ B p65 inhibition, which is critically involved in neuroinflammation and cognitive impairments [ 24 ]. Therefore, microglia memory induced by repeated LPS injections can ameliorate subsequent neuroinflammation, prevent excess damage to the brain in case of recurrent inflammatory stimulation, and consequent cognitive impairments.…”

The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-ĸB induced IDO expression

“…The results suggest that ASA Ⅵ suppressed microglia-mediated neuroinflammation by inhibiting the TLR4/NF-κB signaling pathway (Yu et al 2012). TLR4/NF-κB signaling appears to be the most promising route for IDO elevation in the brain of mice undergoing systemic LPS administration and consequent tryptophan catabolite formations (Hemmati et al 2019).…”

“…Inflammatory cytokines such as IL-1β and TNF-α have been shown to enhance this pathway in microglia by potentiating the expression of the kynurenine pathway's main controller enzyme, indoleamine 2, 3-dioxygenase (IDO), through STAT1 activation (Hemmati et al 2019).…”

Forecasting sensitive targets of the kynurenine pathway in pancreatic adenocarcinoma using mathematical modeling

“…[7][8][9] In the PDAC cell, β-catenin induces IκB kinase β (IKKβ) and nuclear factor kappa B (NFκβ) expression. 10,11 NFκβ p65 12 and interleukin 6 (IL-6) 13 are consecutive molecules of NFκβ in the case of Kynp activity.…”

“…In the PDAC cell, β‐catenin induces IκB kinase β (IKK‐β) and nuclear factor kappa B (NF‐κβ) expression 10,11 . NF‐κβ p65 12 and interleukin 6 (IL‐6) 13 are consecutive molecules of NF‐κβ in the case of Kynp activity. Transforming growth factor beta 1 (TGF‐β1) has been reported as an essential biomarker of the Kynp in PDAC 14‐17 .…”