Pioglitazone improves phagocytic activity of liver recruited macrophages in elderly mice possibly by promoting glucose catabolism

Abstract

Recent studies have revealed that the immunological function of leukocytes is dependent on their cellular metabolism, and some researchers have advocated the beneficial effects of pioglitazone against sepsis in young mice, although bacterial infections are more prevalent in elderly hosts. Here, we investigated pioglitazone’s preventative effect against sepsis induced by intravenous injection of a lethal dose of Escherichia coli in elderly mice (50–60 wk old) and examined its immunological and metabolic effects on liver leukocytes. Pioglitazone improved bacterial elimination in the peripheral blood, lowered serum pro-inflammatory cytokines (TNF-α, IL-12, IFN-γ), and prevented septic death. It also enhanced bacterial elimination in the liver, by increasing the phagocytic and bactericidal activities of liver F4/80+CD11b+ recruited macrophages (Mφ), their CD206 expression and reactive oxygen species production. Quantitative PCR revealed that pioglitazone treatment enhanced gene expression of rate-limiting enzymes for glycolysis in hepatic CD11b+ cells (including neutrophils and recruited Mφ), and their improved phagocytic and bactericidal activities were abolished by glycolysis inhibiting reagents. These findings present the possibility that pioglitazone strengthens the phagocytic and bactericidal activities of liver recruited Mφ and that these immunological activities are closely associated with their glucose catabolism.

Type 2 Diabetic Sepsis Patients Have a Lower Mortality Rate in Pioglitazone Use: A Nationwide 15-Year Propensity Score Matching Observational Study in Taiwan

“…Pioglitazone improving bacterial elimination in the peripheral blood, via inhibition of proinflammatory molecules such as IL-6, TNF, IL-1, and IL-12, has been well documented. It also enhanced bacterial elimination in the liver by increasing the phagocytic and bactericidal activities [11]. Furthermore, accumulated evidence of animal models demonstrated that pioglitazone is effective in the prevention and treatment of sepsis in mice cecal ligation and puncture (CLP) model [35][36][37].…”

“…Accumulating evidence in animal studies demonstrated that PPARc agonists improved the outcomes of sepsis via multiple mechanisms [11]. In the mouse model, pioglitazone administration decreased inflammation and improved survival of sepsis induced by cecal ligation and puncture (CLP) [12].…”

Discovery of an Inhibitor for Bacterial 3-Mercaptopyruvate Sulfurtransferase that Synergistically Controls Bacterial Survival

“…In the present study, we found that these inhibitors inhibit eMST at low micromolar concentrations (Figure 1E), do not interfere with the thiosulfate substrate-based rhodanese activity of eMST, and are inactive against hMST at 400 mM (Figures 2D,1E and 1F). Considering that pioglitazone has been administered at 10 mg/kg or 20 mg/kg for treatment of bacterial infection or other disease in vivo (Javadi et al, 2013;Nakashima et al, 2019), the inhibitory effect of pioglitazone on E. coli survival at micromolar concentrations seems to be rational to explain the (C) Pioglitazone concentration dependently suppresses the generation of reactive sulfane sulfurs in the eMST strain. Mean ± SD (n = 3).…”

Anti-diabetics and antimicrobials: Harmony of mutual interplay

“…Glitazones also exert anti-inflammatory effects through suppression of IL-6 and reduction in circulating CRP levels[ 196 ]. One study reported direct impact of TZDs via increasing phagocytosis by liver recruited macrophages, increased production of ROS in phagocytes and decreased serum pro-inflammatory cytokines (TNF-α, IL-12, IFN-γ)[ 197 ]. It was shown that pioglitazone has antibacterial activity against Streptococcus pneumoniae , E. coli and Klebsiella pneumoniae .…”

“…, antibacterial, anti-mycobacterium, anti-malarial and antiviral, which was reviewed[ 200 ]. However, the mechanism of the antimicrobial activity is not fully understood since prokaryotes lack the PPAR-γ receptor which is the target site for glitazones, the antibacterial activity of glitazones may be owed to thiazolidinedione nucleus[ 197 , 200 ]. Although there are no deep studies on the antimicrobial or anti-virulence activities of glitazones, we predict that their antimicrobial activities are owed to thiazolidinedione nucleus.…”