Triptolide Inhibits Preformed Fibril-Induced Microglial Activation by Targeting the MicroRNA155-5p/SHIP1 Pathway

Abstract

Evidence suggests that various forms of α-synuclein- (αSyn-) mediated microglial activation are associated with the progression of Parkinson’s disease. MicroRNA-155-5p (miR155-5p) is one of the most important microRNAs and enables a robust inflammatory response. Triptolide (T10) is a natural anti-inflammatory component, isolated from a traditional Chinese herb. The objective of the current study was to identify the role and potential regulatory mechanism of T10 in αSyn-induced microglial activation via the miR155-5p mediated SHIP1 signaling pathway. Mouse primary microglia were exposed to monomers, oligomers, and preformed fibrils (PFFs) of human wild-type αSyn, respectively. The expressions of TNFα and IL-1β, measured by enzyme-linked immunosorbent assay (ELISA) and qPCR, demonstrated that PFFs initiated the strongest immunogenicity in microglia. Application of inhibitors of toll-like receptor (TLR) 1/2, TLR4, and TLR9 indicated that PFFs activated microglia mainly via the NF-κB pathway by binding TLR1/2 and TLR4. Treatment with T10 significantly suppressed PFF-induced microglial activation and attenuated the release of proinflammatory cytokines including TNFα and IL-1β. Levels of IRAK1, TRAF6, IKKα/β, p-IKKα/β, NF-κB, p-NF-κB, PI3K, p-PI3K, t-Akt, p-Akt and SHIP1 were measured via Western blot. Levels of miR155-5p were measured by qPCR. The results demonstrated that SHIP1 acted as a downstream target molecule of miR155-5p. Treatment with T10 did not alter the expression of IRAK1 and TRAF6, but significantly decreased the expression of miR155-5p, resulting in upregulation of SHIP1 and repression of NF-κB activity, suggesting inhibition of inflammation and microglial activation. The protective effects of T10 were abolished by the use of SHIP1 siRNA and its inhibitor, 3AC, and miR155-5p mimics. In conclusion, our results demonstrated that treatment with T10 suppressed microglial activation and attenuated the release of proinflammatory cytokines by suppressing NF-κB activity via targeting the miR155-5p/SHIP1 pathway in PFFs-induced microglial activation.

miR-935 Inhibits Oral Squamous Cell Carcinoma and Targets Inositol Polyphosphate-4-phosphatase Type IA (INPP4A)

“…PI3K/Akt pathway is known to play important roles in controlling all these steps (86)(87)(88)(89). The potential targets of miR-155-5p includes PTEN (90) and SHIP1 (91), both of which negatively regulate PI3K/Akt signaling pathway (90,92). Given that miR-935/INPP4A axis could also regulate PI3K/Akt pathway, it is conceivable that targeting both miR-935 and miR-155-5p may lead to better outcomes in OSCC treatment.…”

Anti-apoptosis mechanism of triptolide based on network pharmacology in focal segmental glomerulosclerosis rats

“…Triptolide (TPL) is the most active and effective diterpene lactone epoxide compound isolated from Tripterygium. [4]. TPL has anti-inflammatory, anti-tumor, and immunologic effects on many diseases [4].…”

“…[4]. TPL has anti-inflammatory, anti-tumor, and immunologic effects on many diseases [4]. TPL inhibits the secretion of many cytokines, adhesion molecules, and chemokines and affects the functions of various cells, including dendritic cells and renal tubular epithelial cells [5,6].…”

MicroRNA‐155 deficiency attenuates inflammation and oxidative stress in experimental autoimmune prostatitis in a TLR4‐dependent manner

“…35 In addition, the miR-155-5p/SHIP1 pathway is involved in the inhibitory effect of triptolide on NF-κB activity through preformed fibril (PFF)-induced activation in microglia to decrease the release of proinflammatory cytokines. 36 Zhou et al found that in the presence of ESAT6, miR-155 was upregulated, resulting in the activation of the TLR4 signaling pathway, which could deteriorate the renal injury induced by Mycobacterium tuberculosis in mice. 12 Thus, miR-155 deficiency may inhibit the TLR4/NF-κΒ signaling pathway to exert protective effects in diseases, including CP.…”