rSjP40 suppresses hepatic stellate cell activation by promoting microRNA‐155 expression and inhibiting STAT5 and FOXO3a expression

Abstract

Activation of hepatic stellate cells (HSCs) is the central event of the evolution of hepatic fibrosis. Schistosomiasis is one of the pathogenic factors which could induce hepatic fibrosis. Previous studies have shown that recombinant Schistosoma japonicum egg antigen P40 (rSjP40) can inhibit the activation and proliferation of HSCs. MicroRNA‐155 is one of the multifunctional noncoding RNA, which is involved in a series of important biological processes including cell development, proliferation, differentiation and apoptosis. Here, we try to observe the role of microRNA‐155 in rSjP40‐inhibited HSC activation and explore its potential mechanisms. We found that microRNA‐155 was raised in rSjP40‐treated HSCs, and further studies have shown that rSjP40 enhanced microRNA‐155 expression by inhibiting STAT5 transcription. Up‐regulated microRNA‐155 can down‐regulate the expression of FOXO3a and then participate in rSjP40‐inhibited expression of α‐smooth muscle actin (α‐SMA) and collagen I. Furthermore, we observed microRNA‐155 inhibitor could partially restore the down‐regulation of FOXO3a, α‐SMA and collagen I expression in LX‐2 cells induced by rSjP40. Therefore, our research provides further insight into the mechanism by which rSjP40 could inhibit HSC activation via miR‐155.

Hallmarks of Aging in the Liver

“…The aging mouse has many changes in the transcription network [83,90], including importantly alterations in Forkhead box O (FOXO), a key transcription factor implicated in aging [91]. FOXO influences NO regulation, hyperinsulinemia [92] and activation of HSCs [93] through its effects on downstream genes such as glucose 6-phosphatase, phosphoenolpyruvate carboxykinase, insulin-like growth factor-binding protein 1, PGC-1α, pyruvate Dehydrogenase Kinase 4, and hydroxymethylglutaryl-CoA synthase [94]. FOXO is regulated by NAD + /SIRT1, insulin like growth factor 1 (IGF-1), 5′ adenosine monophosphate-activated protein kinase (AMPK) and oxidative stress, all of which are influenced by aging (Fig.…”

Pathology and molecular mechanisms of Schistosoma japonicum-associated liver fibrosis

“…The first release of Schistosoma japonicum eggs is immature, and the inner envelope of the mature eggs after one week is considered to be the main source of SEA ( De Marco Verissimo et al., 2019 ). SEA is a complex mixture of multiple egg antigens, of which Schistosoma japonicum egg antigen p40 ( Sjp40 ) is one of the components after six weeks of Schistosoma japonicum infection ( Zhu et al., 2018 ; Chen et al., 2019b ). Sjp40 is a marker used for early schistosomiasis diagnosis, and sjp40 inhibits the activation and proliferation of HSCs ( Zhu et al., 2018 ).…”

“…Resting HSCs are located in the Disse region of the subendothelial space and their major function is to stock vitamin A and erythropoietin ( Carson et al., 2018 ; Wang et al., 2022 ). HSCs are activated to myofibroblasts during liver injuries or inflammatory stimulation, which express α-smooth muscle actin ( α-SMA ) and overproduce hydroxyproline-containing collagen leading to massive deposition of ECM ( Yu et al., 2016 ; Zhu et al., 2018 ). Schistosoma infections induce differentiation of HSCs into two functionally distinct cell subtypes, while MHC II - HSCs exhibit a myofibroblast phenotype, and MHC II + HSCs are associated with regulatory T cell development ( Zhou et al., 2017 ).…”

The role of microRNAs in the pathogenesis, grading and treatment of hepatic fibrosis in schistosomiasis

“…Also, miR-15b and miR-16 play important roles in inducing HSC apoptosis by targeting bcl-2 in the caspase signaling pathway [90]; miR-454 was reported to be downregulated in S. japonicum -induced liver fibrosis models and it could participate in inhibiting HSC activation during schistosomiasis-associated liver fibrosis by targeting Smad4 [91]. As a pleiotropic modulator, miR-155 inhibits HSC activation by blocking the ERK1 signaling pathway [92] and inhibits LX-2 cell activation by targeting FOXO3a [93]. During schistosomiasis-associated liver fibrosis, miR-29b-3p is believed to inhibit HSC activation by targeting COL1A1 and COL3A1 in the TGF-β1 signaling pathway [94].…”