Cathepsin B inhibition ameliorates the non-alcoholic steatohepatitis through suppressing caspase-1 activation

Abstract

Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease. NLRP3 inflammasome activation has been widely studied in the pathogenesis of NAFLD. Cathepsin B (CTSB) is a ubiquitous cysteine cathepsin, and the role of CTSB in the progression and development of NAFLD has received extensive concern. However, the exact roles of CTSB in the NAFLD development and NLRP3 inflammasome activation are yet to be evaluated. In the present study, we used methionine choline-deficient (MCD) diet to establish mice NASH model. CTSB inhibitor (CA-074) was used to suppress the expression of CSTB. Expressions of CTSB and caspase-1 were evaluated by immunohistochemical staining. Serum IL-1β and IL-18 levels were also determined. Palmitic acid was used to stimulate Kupffer cells (KCs), and protein expressions of CTSB, NLRP3, ASC (apoptosis-associated speck-like protein containing CARD), and caspase-1 in KCs were detected. The levels of IL-1β and IL-18 in the supernatant of KCs were evaluated by enzyme-linked immunosorbent assay (ELISA). Our results showed that CTSB inhibition improved the liver function and reduced hepatic inflammation and ballooning, and the levels of pro-inflammatory cytokines IL-1β and IL-18 were decreased. The expressions of CTSB and caspase-1 in liver tissues were increased in the NASH group. In in vitro experiments, PA stimulation could increase the expressions of CTSB and NLRP3 inflammasome in KCs, and CTSB inhibition downregulated the expression of NLRP3 inflammasome in KCs, when challenged by PA. Moreover, CTSB inhibition effectively suppressed the expression and activity of caspase-1 and subsequently secretions of IL-1β and IL-18. Collectively, these results suggest that CTSB inhibition limits NLRP3 inflammasome-dependent NASH formation through regulating the expression and activity of caspase-1, thus providing a novel anti-inflammatory signal pathway for the therapy of NAFLD.

Inflammation and tumor progression: signaling pathways and targeted intervention

“…155 For instance, cathepsin S is a cysteine protease involved in the cleavage of elastin and generation of bioactive elastin peptides. 156 Cathepsin B (CatB) is known to have a role in the production of mature IL-1β and TNFα, 157 while cathepsin K (CatK) contributes to the activation of TLR9. 158,159 The regulation of inflammatory mediators can occur at multiple levels, including transcription, mRNA translation, posttranslational modification, and mRNA degradation.…”

Co-expression analysis reveals dysregulated miRNAs and miRNA-mRNA interactions in the development of contrast-induced acute kidney injury

“…Among them, 276 were upregulated in CI-AKI, whereas the remaining 177 were downregulated (S5 Table). These included inflammation related genes Gpnmb (glycoprotein Nmb) [43] and Cstb (cystatin B) [44], cell death related gene Gng7 (G protein subunit gamma 7) [45], as well as the renal protective gene Gstm1 (glutathione S-transferase Mu 1) [46]. These specific genes and their functions merit further investigation.…”

“…For instance, Cstb is a ubiquitous cysteine cathepsin that has been extensively studied in non-alcoholic steatohepatitis. Tang et al observed recently that Cstb might facilitate inflammation and apoptosis by promoting the expression and activity of caspase-1, as well as the secretion of IL-1β and IL-18 [44]. Ephx1 levels were observed to be significantly elevated in the rat kidney following cisplatin treatment, although the function of this protein was not further elucidated [62].…”

The multifaceted role of cathepsins in liver disease

“…Hence, CtsB knockout mice display preserved mitochondrial function, reduced oxidative stress and amelioration of the liver damage during NAFLD (36). CtsB inhibition using Ca074-Me has also been described to reduce hepatic inflammation and improve hepatic function in mice after MCD (Methionine-Choline-Deficient) diet feeding, by limiting NLRP3/caspase-1 activation and IL-1β and IL-18 secretion (37). Interestingly, LDL receptor-related protein-1 (LRP1) participates in cholesterol efflux via HDL secretion and plays a role in CtsD endocytosis (38).…”