Suppression of NLRP3 Inflammasome by Dihydroarteannuin via the HIF‐1α and JAK3/STAT3 Signaling Pathway Contributes to Attenuation of Collagen-Induced Arthritis in Mice

Abstract

Dihydroarteannuin (DHA), the primary element of artemisinin extracted from the traditional Chinese herb Artemisia annua L., has been used in malaria treatment for a long time. Recently, many studies have indicated that DHA also exhibits potent anti-rheumatoid arthritis (RA) activity. In this study, collagen-induced arthritis (CIA) in DBA/1J mice and inflammatory model in THP-1 cells were established to evaluate the modulatory effects of DHA on joint destruction and to explore the underlying mechanisms. Our results showed that DHA decreased the serum levels of IL-1β and IL-6, alleviated paw oedema, and reduced bone destruction in DBA/1J mice with CIA. Further exploration with the inflammatory model in THP-1 cells indicated that DHA reduced the protein expression of hypoxia‐inducible factor (HIF)‐1α and the phosphorylation in Janus kinase (JAK) 3 and signal transducer and activator of transcription (STAT) 3 protein, which resulted in a decrease in NOD-like receptor protein (NLRP) 3 expression and interleukin (IL)-1β release. Consequentially, the inflammatory activation in THP-1 cells was inhibited. Therefore, we concluded that DHA efficiently alleviated the inflammation and arthritic symptoms in CIA mice and downregulated inflammation in part by inhibiting NLRP3 expression via the HIF‐1α and JAK3/STAT3 signaling pathway. Thus, DHA may be considered as a potential therapeutic agent in RA treatment.

Suppression of Macrophage Activation by Sodium Danshensu via HIF-1α/STAT3/NLRP3 Pathway Ameliorated Collagen-Induced Arthritis in Mice

“…A previous study has shown that HIF-1α expression was evoked by LPS stimulation in vitro [ 34 , 35 ]. Similarly, HIF-1α expression was sharply increased by LPS stimulation in our study.…”

“…The process for CIA induction has been described previously [ 34 ]. In brief, bovine type II collagen (Chondrex, Woodinville, WA, USA, Cat#20021) and complete Freund’s adjuvant (Chondrex, Cat#7001) were fully emulsified.…”

“…Micro-CT scanning with Skyscan 1176 Micro-CT Imaging System (Skyscan, Belgium) was used to generate the two- and three-dimensional images of joints in the knee and ankle [ 34 ]. The scanning parameters settings were as follow: voltage, 80 kV; source current, 88 μA; and pixel size 4 μm.…”

Emerging role of hypoxia-inducible factor-1α in inflammatory autoimmune diseases: A comprehensive review

“…IL-17 induces defective autophagy through interacting with STAT3/HIF-1α and causes inflammatory death of keloid fibroblasts ( 27 ). In addition, Janus kinase (JAK) signaling, an important upstream activator of STAT3, directly promotes NLRP3 expression and IL-1β secretion to aggravate inflammation ( 28 ). The classical mitogen-activated protein kinases (MAPK) and regulated extracellular protein kinases (ERK) pathways adapt to hypoxia, and then activate HIF-1α, thereby protecting cell development and avoiding oxidative damage ( 29 , 30 ).…”

Critical Functions of Histone Deacetylases (HDACs) in Modulating Inflammation Associated with Cardiovascular Diseases

“…Furthermore, the expression of HIF-1α was downregulated in cells silenced with HDAC 4 by siRNA [ 37 ]. HIF-1a is a key transcription factor in the pathogenesis of various inflammatory diseases including RA, suggesting a link between HDAC 4 and inflammatory diseases [ 38 ].…”