Statins repress needle-like carbon nanotube- or cholesterol crystal-stimulated IL-1 β production by inhibiting the uptake of crystals by macrophages

In this study, we evaluated the effect of statins on crystal-induced IL-1β production in macrophages. We found that various statins, including pitavastatin, atorvastatin, fluvastatin, and lovastatin, but not squalene synthase inhibitor, repressed IL-1β release upon MWCNT stimulation. In addition, IL-1β production induced by cholesterol crystals and MSU crystals, but not by ATP or nigericin, was diminished. MWCNT-stimulated IL-1β release was dependent on the expression of NLRP3, but not AIM2, NLRC4, or MEFV. Statin-induced repression was accompanied by reduced levels of mature caspase-1 and decreased uptake of MWCNT into cells. Supplementation of mevalonate, geranylgeranyl pyrophosphate, or farnesyl pyrophosphate prevented the reduction in IL-1β release, suggesting a crucial role of protein prenylation, but not cholesterol synthesis. The statin-induced repression of MWCNT-elicited IL-1β release was observed in THP-1 derived and mouse peritoneal macrophages, but not in bone marrow-derived macrophages, where statins act in synergy with lipopolysaccharide to enhance the expression of IL-1β precursor protein. In summary, we describe a novel anti-inflammatory mechanism through which statins repress mature IL-1β release induced by pathogenic crystals and nanoneedles by inhibiting the internalization of crystals by macrophages.PMID:33930349 | DOI:10.1016/j.bcp.2021.114580
Source: Biochemical Pharmacology - Category: Drugs & Pharmacology Authors: Source Type: research