Verapamil and tangeretin enhances the M1 macrophages to M2 type in lipopolysaccharide-treated mice and inhibits the P-glycoprotein expression by downregulating STAT1/STAT3 and upregulating SOCS3

• Published in: International immunopharmacology 2024-05, Vol.133, p.112153-112153, Article 112153
• Main Authors: Kundu, Ayantika, Ghosh, Pratiti, Bishayi, Biswadev
• Format: Article
• Language: English
• Subjects: LPS; M1 and M2 macrophages; P-glycoprotein; ROS; Sepsis; STAT3, SOCS3, Tangeritin; Verapamil
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2024.112153

•LPS-induced sepsis involves immune cells and signaling molecules, with macrophage polarization and ROS production being key factors.•PGP, expressed in murine macrophages, is responsible for drug efflux.•Verapamil and tangeretin, both found in LPS-induced inflammatory diseases, improve tissue antioxidant capacity by enhancing SOD, CAT, GRX, and GSH levels.•They also inhibit P-glycoprotein expression by downregulating STAT1/STAT3 and upregulating SOCS3 expression in macrophages.•Both verapamil and tangeretin show protective effects by suppressing iNOS, COX-2, oxidative stress, and NF-κB p65 signaling. LPS induced sepsis is a complex process involving various immune cells and signaling molecules. Dysregulation of macrophage polarization and ROS production contributed to the pathogenesis of sepsis. PGP is a transmembrane transporter responsible for the efflux of a number of drugs and also expressed in murine macrophages. Natural products have been shown to decrease inflammation and expression of efflux transporters. However, no treatment is currently available to treat LPS induced sepsis. Verapamil and Tangeretin also reported to attenuate lipopolysaccharide-induced inflammation. However, the effects of verapamil or tangeretin on lipopolysaccharide (LPS)-induced sepsis and its detailed anti-inflammatory mechanism have not been reported. Here, we have determined that verapamil and tangeretin protects against LPS-induced sepsis by suppressing M1 macrophages populations and also through the inhibition of P-glycoprotein expression via downregulating STAT1/STAT3 and upregulating SOCS3 expression in macrophages. An hour before LPS (10 mg/kg) was administered; mice were given intraperitoneal injections of either verapamil (5 mg/kg) or tangeretin (5 mg/kg). The peritoneal macrophages from different experimental groups of mice were isolated. Hepatic, pulmonary and splenic morphometric analyses revealed that verapamil and tangeretin decreased the infiltration of neutrophils into the tissues. Verapamil and tangeritin also enhanced the activity of SOD, CAT, GRX and GSH level in all the tissues tested. verapamil or tangeretin pre-treated mice shifted M1 macrophages to M2 type possibly through the inhibition of P-glycoprotein expression via downregulating STAT1/STAT3 and upregulating SOCS3 expression. Hence, both these drugs have shown protective effects in sepsis via suppressing iNOS, COX-2, oxidative stress and NF-κB signaling in macrophages. Therefore, in our study we c