Triptolide Modulates TREM-1 Signal Pathway to Inhibit the Inflammatory Response in Rheumatoid Arthritis

Abstract

Triptolide (TP), an active component isolated from Tripterygiumwilfordii Hook F, has therapeutic potential against rheumatoid arthritis (RA). However, the underlying molecular mechanism has not been fully elucidated. The aim of this study is to investigate the mechanisms of TP acting on RA by combining bioinformatics analysis with experiment validation. The human protein targets of TP and the human genes of RA were found in the PubChem database and NCBI, respectively. These two dataset were then imported into Ingenuity Pathway Analysis (IPA) software online, and then the molecular network of TP on RA could be set up and analyzed. After that, both in vitro and in vivo experiments were done to further verify the prediction. The results indicated that the main canonical signal pathways of TP protein targets networks were mainly centered on cytokine and cellular immune signaling, and triggering receptors expressed on myeloid cells (TREM)-1 signaling was searched to be the top one shared signaling pathway and involved in the cytokine and cellular immune signaling. Further in vitro experiments indicated that TP not only remarkably lowered the levels of TREM-1 and DNAX-associated protein (DAP)12, but also significantly suppressed the activation of janus activating kinase (JAK)2 and signal transducers and activators of transcription (STAT)3. The expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in lipopolysaccharides (LPS)-stimulated U937 cells also decreased after treatment with TP. Furthermore, TREM-1 knockdown was able to interfere with the inhibition effects of TP on these cytokines production. In vivo experiments showed that TP not only significantly inhibited the TREM-1 mRNA and DAP12 mRNA expression, and activation of JAK2 and STAT3 in ankle of rats with collagen-induced arthritis (CIA), but also remarkably decreased production of TNF-α, IL-1β and IL-6 in serum and joint. These findings demonstrated that TP could modulate the TREM1 signal pathway to inhibit the inflammatory response in RA.

Blocking triggering receptor expressed on myeloid cells-1 attenuates lipopolysaccharide-induced acute lung injury via inhibiting NLRP3 inflammasome activation

“…TREM-1 activation can amplify TLRs and NLRs signaling to promote the production of pro-inflammatory cytokines, degranulation of neutrophils, and phagocytosis 111213. Depletion or blocking TREM-1 has shown protective effects in sepsis, ischemia-reperfusion, pancreatitis, inflammatory bowel diseases, Fungal Keratitis and arthritis14151617181920. Our previous study found that the expression of TREM-1 in LPS-induced ALI mice lung and macrophages are significantly increased, suggesting an important role of TREM-1 in ALI2122.…”

Mitochondrial Electron Transport Chain Inhibition Suppresses LPS-Induced Inflammatory Responses via TREM1/STAT3 Pathway in BV2 Microglia

“…Accumulating evidence has indicated that TREM1 is an amplifier of the inflammatory process, while TREM2 has anti-inflammatory activity (22,26,28,29). Inhibition of TREM1 has shown to attenuate the inflammation in several animal models of diseases, such as fatty liver diseases, rheumatoid arthritis or pneumonia (28,30,31). Our current study has shown that the three mitochondrial ETC inhibitors significantly decreased both the mRNA and protein levels of TREM1 in LPS-treated BV2 microglia, suggesting that the mitochondrial ETC inhibitor-produced suppression of the LPS-induced microglial activation results at least partially from its capacity to decrease the TREM1 level.…”

The triptolide‐induced apoptosis of osteoclast precursor by degradation of cIAP2 and treatment of rheumatoid arthritis of TNF‐transgenic mice

“…The current researches on the mechanism of TPL in the treatment of RA mainly includes the following aspects: Wang et al () applied TPL to collagen‐induced RA mice, suggesting that TPL could improve arthritis symptoms of RA by inhibiting the secretion of inflammatory cytokines by T lymphocytes; Kong et al () proposed that TPL could inhibit the inflammation of RA by blocking the angiogenesis at the inflammatory site; Su, Sun, Ao, and Zhao () proposed that TPL could mediate the apoptosis of fibroblast‐like synoviocytes and inhibit their inflammation to improve the symptoms of RA. Fan et al () found that TPL could inhibit the degree of inflammation through TREM‐1 signaling pathway; Liu et al () proposed that TPL could block RANKL/RANK/OPG signaling pathways in collagen‐induced RA mice to prevent the formation of OCs from OCPs, thereby inhibiting bone destruction of RA. However, some studies have shown that RANKL inhibitors were unable to prevent the formation of RA or significantly improve its clinical symptoms (Ferrari‐Lacraz & Ferrari, ).…”