The dysregulation of NLRP3 inflammasome can cause uncontrolled inflammation and drive the development of a wide variety of human diseases, but the medications targeting NLRP3 inflammasome are not available in clinic. Here, we show that tranilast (TR), an old anti‐allergic clinical drug, is a direct NLRP3 inhibitor. TR inhibits NLRP3 inflammasome activation in macrophages, but has no effects on AIM2 or NLRC4 inflammasome activation. Mechanismly, TR directly binds to the NACHT domain of NLRP3 and suppresses the assembly of NLRP3 inflammasome by blocking NLRP3 oligomerization. In vivo experiments show that TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3 inflammasome‐related human diseases, including gouty arthritis, cryopyrin‐associated autoinflammatory syndromes, and type 2 diabetes. Furthermore, TR is active ex vivo for synovial fluid mononuclear cells from patients with gout. Thus, our study identifies the old drug TR as a direct NLRP3 inhibitor and provides a potentially practical pharmacological approach for treating NLRP3‐driven diseases.
Theranostic
systems combining fluorescence imaging in the second
near-infrared window (NIR-II, 1000–1700 nm) and photothermal
therapy (PTT) under safe laser fluence have great potential in preclinical
research and clinical practice, but the development of such systems
with sufficient effective NIR-II brightness and excellent photothermal
properties is still challenging. Here we report a theranostic system
based on semiconducting polymer nanoparticles (L1057 NPs) for NIR-II
fluorescence imaging and PTT under a 980 nm laser irradiation, with
low (25 mW/cm2) and high (720 mW/cm2) laser
fluence, respectively. Taking into consideration multiple parameters
including the extinction coefficient, the quantum yield, and the portion
of emission in the NIR-II region, L1057 NPs have much higher effective
NIR-II brightness than most reported organic NIR-II fluorophores.
The high brightness, together with good stability and excellent biocompatibility,
allows for real-time visualization of the whole body and brain vessels
and the detection of cerebral ischemic stroke and tumors with high
clarity. The excellent photothermal properties and high maximal permissible
exposure limit at 980 nm allow L1057 NPs for PTT of tumors under safe
laser fluence. This study demonstrates that L1057 NPs behave as an
excellent theranostic system for NIR-II imaging and PTT under safe
laser fluence and have great potential for a wide range of biomedical
applications.
The NLRP3 inflammasome can sense different pathogens or danger signals, and has been reported to be involved in the development of many human diseases. Potassium efflux and mitochondrial damage are both reported to mediate NLRP3 inflammasome activation, but the underlying, orchestrating signaling events are still unclear. Here we show that chloride intracellular channels (CLIC) act downstream of the potassium efflux-mitochondrial reactive oxygen species (ROS) axis to promote NLRP3 inflammasome activation. NLRP3 agonists induce potassium efflux, which causes mitochondrial damage and ROS production. Mitochondrial ROS then induces the translocation of CLICs to the plasma membrane for the induction of chloride efflux to promote NEK7–NLRP3 interaction, inflammasome assembly, caspase-1 activation, and IL-1β secretion. Thus, our results identify CLICs-dependent chloride efflux as an essential and proximal upstream event for NLRP3 activation.
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