Caspase-11 promotes renal fibrosis by stimulating IL-1β maturation via activating caspase-1

Abstract

Caspase-11 is a key upstream modulator for activation of inflammatory response under pathological conditions. In this study, we investigated the roles of caspase-11 in the maturation of interleukin-1β (IL-1β) and development of renal interstitial fibrosis in vivo and in vitro. Mice were subjected to unilateral ureteral obstruction (UUO). The mice were treated with either caspase-11 inhibitor wedelolactone (Wed, 30 mg/kg/day, ig) for 7 days or caspase-11 siRNA (10 nmol/20 g body weight per day, iv) for 14 days. The mice were euthanized on day 14, their renal tissue and blood sample were collected. We found that the obstructed kidney had significantly higher caspase-11 levels and obvious tubular injury and interstitial fibrosis. Treatment with Wed or caspase-11 siRNA significantly mitigated renal fibrosis in UUO mice, evidenced by the improved histological changes. Furthermore, caspase-11 inhibition significantly blunted caspase-1 activation, IL-1β maturation, transforming growth factor-β (TGF-β), fibronectin, and collagen I expressions in the obstructed kidney. Renal tubular epithelial NRK-52E cells were treated in vitro with angiotensin (Ang, 1 μmol/L), which stimulated caspase-11 activation and IL-1β maturation. Treatment with IL-1β (20 ng/ml) significantly increased the expression of TGF-β, fibronectin, and collagen I in the cells. Ang II-induced expression of TGF-β, fibronectin, and collagen I were suppressed by caspase-11 siRNA or Wed. Finally, we revealed using co-immunoprecipitation that caspase-11 was able to interact with caspase-1 in NRK-52E cells. These results suggest that caspase-11 is involved in UUO-induced renal fibrosis. Elevation of caspase-11 in the obstructed kidney promotes renal fibrosis by stimulating caspase-1 activation and IL-1β maturation.

Epigallocatechin‐3‐Gallate Attenuates Microglial Inflammation and Neurotoxicity by Suppressing the Activation of Canonical and Noncanonical Inflammasome via TLR4/NF‐κB Pathway

“…To fully understand the possible role of TLR4/NF‐κB pathway in caspase‐1‐dependent inflammatory responses, BV2 cells were pretreated with an IKK inhibitor wedelolactone, which was also used as a specific inhibitor of caspase‐11 . As shown in Figure C,D, consistent with the efficacy of EGCG, wedelolactone significantly reduced the expressions of p‐IKK/IKK, p‐NF‐κB/NF‐κB, caspase‐11 p26, caspase‐1 p20, cleaved IL‐1β, and cleaved IL‐18.…”

Effect and Regulation of the NLRP3 Inflammasome During Renal Fibrosis

“…Crystals deposited within the renal tubules activate the NLRP3 inflammasome and downstream-related signaling molecules, ultimately causing renal tubular epithelial pyroptosis (Hutton et al, 2016). A recent study also found that caspase-11 stimulates the maturation of IL-1 to promote renal fibrosis by activating caspase-1 (Miao et al, 2019). It can be observed that pyroptosis also participates in the progression of renal fibrosis.…”

Pyroptosis: A New Frontier in Kidney Diseases

“…Increased expression of NLRP3 and caspase-1, as well as enhanced release of the IL-1 β and IL-18 inflammatory bodies, was observed in both renal biopsy specimens of UUO mice and humans with UUO (unilateral ureteral occlusion), whereas the degree of renal fibrosis was markedly alleviated in NLRP3 −/− mice [ 72 , 73 ]. In a long-term study, Miao et al [ 74 ] found in 2018 that in UUO mice caspase-11 could activate caspases-1, enhance the release of inflammatory factors, and promote the progression of renal fibrosis; pyroptosis is a UUO mediated by the atypical caspase-11 pathway. Necrotic DNA can exacerbate UUO-induced kidney disease and injury by activating the inflammatory body AIM2 [ 75 ].…”