Iguratimod Alleviates Experimental Sjögren's Syndrome by Inhibiting NLRP3 Inflammasome Activation.

Iguratimod (T-614) is a compound widely used as anti-rheumatic drug. This study investigated the effect and underlying mechanism of T-614 on experimental Sjögren's syndrome (ESS). ESS mice model was established by injection of submandibular gland protein. Mice were randomly divided into control, experimental Sjögren's syndrome (ESS), ESS + T-614 (10 mg/kg), ESS + T-614 (20 mg/kg), and ESS + T-614 (30 mg/kg) groups. Human submandibular gland (HSG) were cultured with 0, 0.5, 5, or 50 µg/ml T-614 in the absence or presence of interferon-α (IFN-α). Haematoxylin and eosin (H&E) and cytokine levels were used to detect immune cells activation in submandibular glands. Apoptosis in submandibular glands tissues and cells was determined by TUNEL and flow cytometry. Apoptosis and NLRP3 inflammasome-related proteins were detected by western blotting. T-614 treatment attenuated submandibular gland damage in ESS mice. T-614 administration inhibited submandibular gland cell apoptosis in ESS mice. Furthermore, T-614 blocked inflammatory factor levels and NLRP3 inflammasome activation in the submandibular glands. In vitro, results corroborated that T-614 could protect HSG cells from IFN-α-induced cell apoptosis and inflammation by inhibiting NLRP3 inflammasome activation. Our results expounded that T-614 alleviated ESS by inhibiting NLRP3 inflammasome activation.

Myriocin enhances the clearance of M. tuberculosis by macrophages through the activation of PLIN2.

Myriocin is an inhibitor of de novo synthesis of sphingolipids and ceramides. In this research, we showed myriocin could significantly reduce Mtb burden and histopathological inflammation in mice. However, the underlying mechanism remains unclear. RNA-seq analysis revealed a significant increase in gene expression of PLIN2/CD36/CERT1 after myriocin treatment. The reduced bactericidal burden was only reversed after silencing the lipid droplets (LDs) surface protein PLIN2. This suggests that myriocin enhances the ability of macrophages to clear Mtb depending on the PLIN2 gene, which is part of the PPARγ pathway. Indeed, we observed a significant increase in the number of LDs following myriocin treatment.IMPORTANCEMycobacterium tuberculosis has the ability to reprogram host cell lipid metabolism and alter the antimicrobial functions of infected macrophages. The sphingolipids, such as ceramides, are the primary host lipids utilized by the bacteria, making the sphingomyelinase/ceramide system critical in Mtb infections. Surprisingly, the antimicrobial effect of myriocin was found to be independent of its role in reducing ceramides, but instead, it depends on the lipid droplets surface protein PLIN2. Our findings provide a novel mechanism for how myriocin enhances Mtb clearance in macrophages.