Timosaponin BⅡ alleviates DSS-induced ulcerative colitis in mice by
inhibiting NLRP3
Abstract
Background and Purpose Inhibition of NLRP3 inflammasome plays a critical
therapeutic potential in the colonic inflammatory responses. The
Timosaponin BⅡ (TBⅡ) isolated from the traditional Chinese medicine
Anemarrhena asphodeloides has outstanding anti-inflammatory effects in a
variety of diseases. Here, we investigated the protective effects of TBⅡ
against dextran sulfate sodium (DSS)-induced ulcerative colitis in mice.
Experimental Approach Wild-type (WT) and NLRP3 knockout (NLRP3-/-) mice
were applied to evaluate the protective effects of TBⅡ in DSS-induced
mice colitis. The role of TBⅡ in LPS+ATP-induced cell model was
evaluated by inhibiting or overexpressing NLRP3. RNA-seq, ELISA, western
blots, immunofluorescence staining and the expression analysis by qPCR
were performed to examine the alterations of colonic NLRP3 expression in
colon tissues and cells, respectively. Key Results In mice with
DSS-induced ulcerative colitis, TBⅡ treatment repaired the intestinal
mucosal barrier and alleviated colonic inflammation. RNA-seq analysis
and levels of protein expression demonstrated that TBⅡ could prominently
inhibit NLRP3 signaling. TBⅡ-mediated NLRP3 inhibition was associated
with the alleviation of intestinal permeability and the inflammatory
response via blocking the communication between epithelial cells and
macrophages. However, pharmacological inhibition of NLRP3 or NLRP3
overexpression significantly impaired TBⅡ-mediated the anti-inflammatory
effect. Mechanistically, TBⅡ-mediated NLRP3 inhibition may be partially
associated with the suppression of NF-κB. Conclusion and Implications
TBⅡ exerted a prominent protective effect against colitis by impeding
the crosstalk between epithelial cells and macrophages, partially in the
NLRP3-mediated the inhibitory mechanism. These beneficial effects could
make TBⅡ a promising drug for relieving colitis.