Shikonin Suppresses NLRP3 and AIM2 Inflammasomes by Direct Inhibition of Caspase-1

Abstract

Shikonin is a highly lipophilic naphtoquinone found in the roots of Lithospermum erythrorhizon used for its pleiotropic effects in traditional Chinese medicine. Based on its reported antipyretic and anti-inflammatory properties, we investigated whether shikonin suppresses the activation of NLRP3 inflammasome. Inflammasomes are cytosolic protein complexes that serve as scaffolds for recruitment and activation of caspase-1, which, in turn, results in cleavage and secretion of proinflammatory cytokines IL-1β and IL-18. NLRP3 inflammasome activation involves two steps: priming, i.e. the activation of NF-κB pathway, and inflammasome assembly. While shikonin has previously been reported to suppress the priming step, we demonstrated that shikonin also inhibits the second step of inflammasome activation induced by soluble and particulate NLRP3 instigators in primed immortalized murine bone marrow-derived macrophages. Shikonin decreased NLRP3 inflammasome activation in response to nigericin more potently than acetylshikonin. Our results showed that shikonin also inhibits AIM2 inflammasome activation by double stranded DNA. Shikonin inhibited ASC speck formation and caspase-1 activation in murine macrophages and suppressed the activity of isolated caspase-1, demonstrating that it directly targets caspase-1. Complexing shikonin with β-lactoglobulin reduced its toxicity while preserving the inhibitory effect on NLRP3 inflammasome activation, suggesting that shikonin with improved bioavailability might be interesting for therapeutic applications in inflammasome-mediated conditions.

WITHDRAWN: Role of Short-wavelength Blue Light in the Formation of Cataract and Expression of Caspase-1, -11 and Gasdermin D in rat Lens Epithelium Cells: Insight into the Novel Pathogenesis of Cataract.

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MCMV triggers ROS/NLRP3-associated inflammasome activation in the inner ear of mice and cultured spiral ganglion neurons, contributing to sensorineural hearing loss

“…The canonical inflammasome includes NLR (including NLRP1, NLRP3 and NLRC4) and non-NLR (e.g. AIM2) types, which is mediated by activation of caspase-1 in response to pathogen-associated molecular patterns and damage-associated molecular pattern molecules ( 24 , 25 ). Sester et al ( 26 ) reported that AIM2 antagonist protein p202 had a high expression and low IL-1β output in response to transfected DNA and mouse CMV infection in an autoimmune hemolytic anemia model.…”

Pyroptosis, a novel mechanism implicated in cataracts

“…Caspase-1 also mediates proinflammatory programmed cell death, also termed pyroptosis, in response to exogenous and endogenous stimuli to protect cells. Caspase-1 is not only activated in immune cells, but is also activated in epithelial and mesenchymal cells (26), and dysfunction of caspase-1 is closely associated with various diseases (27,28). However, whether pyroptosis of lens epithelial cells is implicated in the initiation and progression of non-congenital cataracts in humans remains to be established.…”