PROTAC based STING degrader attenuates acute colitis by inhibiting macrophage M1 polarization and intestinal epithelial cells pyroptosis mediated by STING-NLRP3 axis.
Int Immunopharmacol
; 141: 112990, 2024 Nov 15.
Article
in En
| MEDLINE
| ID: mdl-39223062
ABSTRACT
Inflammatory bowel diseases (IBDs) are chronic, relapsing, and inflammatory disorders of the gastrointestinal tract characterized by abnormal immune responses. Recently, STING has emerged as a promising therapeutic target for various autoinflammatory diseases. However, few STING-selective small molecules have been investigated as novel strategies for IBD. In this study, we sought to examine the effects of PROTAC-based STING degrader SP23 on acute colitis and explore its underlying mechanism. SP23 treatment notably alleviates dextran sulfate sodium (DSS)-induced colitis. Pharmacological degradation of STING significantly reduced the production of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6, and inhibited macrophage polarization towards the M1 type. Furthermore, SP23 administration decreased the loss of tight junction proteins, including ZO-1, occludin, and claudin-1, and downregulated STING and NLRP3 signaling pathways in intestinal inflammation. In vitro, STING activated NLRP3 inflammasome-mediated pyroptosis in intestinal epithelial cells, which could be abrogated by SP23 and STING siRNA intervention. In conclusion, these findings provide new evidence for STING as a novel therapeutic target for IBD, and reveal that hyperactivation of STING could exaggerate colitis by inducing NLRP3/Caspase-1/GSDMD axis mediated intestinal epithelial cells pyroptosis.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dextran Sulfate
/
Colitis
/
Pyroptosis
/
NLR Family, Pyrin Domain-Containing 3 Protein
/
Macrophages
/
Membrane Proteins
/
Mice, Inbred C57BL
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Int Immunopharmacol
Journal subject:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Netherlands