Stressed and Inflamed, Can GSK3 Be Blamed?

Abstract

Psychological stress has a pervasive influence on our lives. In many cases adapting to stress strengthens organisms, but chronic or severe stress is usually harmful. One surprising outcome of psychological stress is activation of an inflammatory response, resembling inflammation caused by infection or trauma. Excessive psychological stress and the consequential inflammation in the brain can increase susceptibility to psychiatric diseases, such as depression, and impair learning and memory, including in some patients with cognitive deficits. An emerging target to control detrimental outcomes of stress and inflammation is glycogen synthase kinase-3 (GSK3). GSK3 promotes inflammation, partly by regulating key transcription factors in the inflammation signaling pathway, and GSK3 can impair learning by promoting inflammation and by inhibiting long term potentiation (LTP). Drugs inhibiting GSK3 may prove beneficial for controlling mood and cognitive impairments caused by excessive stress and the associated neuroinflammation.

FGF21 Attenuates High-Fat Diet-Induced Cognitive Impairment via Metabolic Regulation and Anti-inflammation of Obese Mice

“…To explore the potential signaling regulation of rFGF21, we then examined the Akt/GSK-3β pathway alteration. It has been known that Akt deactivation and GSK-3β activation play dominant roles in promoting neuroinflammation [69, 70]. We found that Akt was deactivated by reducing its phosphorylation, while GSK- 3β was activated by decreasing its phosphorylation in hippocampal tissues of HFD mice; however, rFGF21 treatment rescued Akt deactivation and reversed GSK-3β activation status (Fig.…”

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

“…GSK3 acts a potent driver of inflammation, rendering GSK3 inhibitors a promising target of anti-inflammatory research [17,121]. It is well established that enzymatically active GSK3 acts as a crucial positive regulator of pro-inflammatory cytokines (e.g., TNF, interleukin (IL-)1β, IL-6 [15], IL-17, IL-18 [122], IL-23 [94], IL-12, IFN-γ [17]), chemokines (IL-8 [122], C-C motif chemokine ligand (CCL) 2 [17], 3, 4 [123], and 12, C-X-C motif chemokine ligand (CXCL) 1, 2, 5 [17], and 10 [124]), and further pro-inflammatory mediators (e.g., nitric oxide (NO) [125] or prostaglandin E2 [126]). Vice versa, anti-inflammatory cytokines, such as IL-2 [127], IL-10 [90], IL-22 [128], IL-33 [129], and IL-1 receptor antagonist [130], are negatively regulated by GSK3.…”

“…In an alternative GSK3α KO model, mice were also viable but characterized by higher body weight, heavier organs (especially brain, heart, and testis), male infertility, and slightly reduced lifespan [136]. Interestingly, despite a multitude of indications that GSK3 has an essential influence on inflammatory processes [17,121], GSK3α KO organisms are not characterized by significant signs of altered immune reactions, implying that GSK3β may be the more prominent paralog with respect to immune regulation.…”

“…Because of its remarkable impact on a variety of physiological key processes [191], GSK3 inhibition has been early regarded as a promising approach within the treatment of serious common diseases (also including inflammation or inflammatory components [17]), such as neurological [192] and cancerous [193] diseases. Though the initial high hopes have not been fully realized, GSK3 inhibitors are still under clinical investigation [194].…”

“…GSK3 also plays a role in the pathogenesis of common diseases, e.g., neurological/neurodegenerative diseases [13,15]; diabetes mellitus [16]; inflammatory diseases [17], such as rheumatoid arthritis [18]; and different types of cancer [19]. Moreover, GSK3 is also of priming phosphorylation has to be mediated by another kinase, GSK3 is able to perform multiple successive phosphorylation steps at substrates containing a series of adjacent consensus sequences, thus generating its own priming phosphorylation for further phosphorylation events [38].…”