GSP1-111 Modulates the Microglial M1/M2 Phenotype by Inhibition of Toll-like Receptor 2: A Potential Therapeutic Strategy for Depression

• Published in: International journal of molecular sciences Vol. 25; no. 19; p. 10594
• Main Authors: Kim, Ryeong-Eun, Mabunga, Darine Froy, Boo, Kyung-Jun, Kim, Dong Hyun, Han, Seol-Heui, Shin, Chan Young, Kwon, Kyoung Ja
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-10-2024; MDPI
• Subjects: Alzheimer's disease; Amyotrophic lateral sclerosis; Animals; Brain; Chemokines; Cytokines; Cytokines - metabolism; depression; Depression - drug therapy; Depression - metabolism; Depression, Mental; Development and progression; Disease Models, Animal; Drug therapy; Genetic aspects; Genotype & phenotype; Health aspects; Immune response; Interleukins; Kinases; Lipopolysaccharides; Major depressive disorder; Male; Mental depression; Mice; Mice, Inbred C57BL; microglia; Microglia - drug effects; Microglia - metabolism; Mitochondrial DNA; Nervous system diseases; neuroinflammation; Neuroinflammatory Diseases - drug therapy; Neuroinflammatory Diseases - metabolism; Neurological disorders; Neurons; Peptides; Peptides - pharmacology; Phenotype; Physiological aspects; Protein expression; Proteins; RNA; Signal transduction; Signal Transduction - drug effects; therapeutics; toll-like receptor 2; Toll-Like Receptor 2 - metabolism; Toxicity; Tumor necrosis factor-TNF; South Korea; therapeutics; depression; neuroinflammation; microglia; toll-like receptor 2
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms251910594

Neuroinflammation plays a vital role in neurodegenerative diseases and neuropsychiatric disorders, and microglia and astrocytes chiefly modulate inflammatory responses in the central nervous system (CNS). Toll-like receptors (TLRs), which are expressed in neurons, astrocytes, and microglia in the CNS, are critical for innate immune responses; microglial TLRs can regulate the activity of these cells, inducing protective or harmful effects on the surrounding cells, including neurons. Therefore, regulating TLRs in microglia may be a potential therapeutic strategy for neurological disorders. We examined the protective effects of GSP1-111, a novel synthetic peptide for inhibiting TLR signaling, on neuroinflammation and depression-like behavior. GSP1-111 decreased TLR2 expression and remarkably reduced the mRNA expression of inflammatory M1-phenotype markers, including tumor necrosis factor (TNF)α, interleukin (IL)-1β, and IL-6, while elevating that of the M2 phenotype markers, Arg-1 and IL-10. In vivo, GSP1-111 administration significantly decreased the depression-like behavior induced by lipopolysaccharide (LPS) in a forced swim test and significantly reduced the brain levels of M1-specific inflammatory cytokines (TNFα, IL-1β, and IL-6). GSP1-111 prevented the LPS-induced microglial activation and TLR2 expression in the brain. Accordingly, GSP1-111 prevented inflammatory responses and induced microglial switching of the inflammatory M1 phenotype to the protective M2 phenotype. Thus, GSP1-111 could prevent depression-like behavior by inhibiting TLR2. Taken together, our results suggest that the TLR2 pathway is a promising therapeutic target for depression, and GSP1-111 could be a novel therapeutic candidate for various neurological disorders.