Bcl-3 regulates T cell function through energy metabolism.

BACKGROUND: Bcl-3 is a member of the IκB protein family and an essential modulator of NF-κB activity. It is well established that Bcl-3 is critical for the normal development, survival and differentiation of adaptive immune cells, especially T cells. However, the regulation of immune cell function by Bcl-3 through metabolic pathways has rarely been studied. RESULTS: In this study, we explored the role of Bcl-3 in the metabolism and function of T cells via the mTOR pathway. We verified that the proliferation of Bcl-3-deficient Jurkat T cells was inhibited, but their activation was promoted, and Bcl-3 depletion regulated cellular energy metabolism by reducing intracellular ATP and ROS production levels and mitochondrial membrane potential. Bcl-3 also regulates cellular energy metabolism in naive CD4+ T cells. In addition, the knockout of Bcl-3 altered the expression of mTOR, Akt, and Raptor, which are metabolism-related genes, in Jurkat cells. CONCLUSIONS: This finding indicates that Bcl-3 may mediate the energy metabolism of T cells through the mTOR pathway, thereby affecting their function. Overall, we provide novel insights into the regulatory role of Bcl-3 in T-cell energy metabolism for the prevention and treatment of immune diseases.

A fresh pH-responsive imipenem-loaded nanocarrier against Acinetobacter baumannii with a synergetic effect.

In recent years, the treatment of Acinetobacter baumannii infections has become a pressing clinical challenge due to its increasing incidence and its serious pathogenic risk. The research and development of new antibacterial agents for A. baumannii have attracted the attention of the scientific community. Therefore, we have constructed a new pH-responsive antibacterial nano-delivery system (Imi@ZIF-8) for the antibacterial treatment of A. baumannii. Due to its pH-sensitive characteristics, the nano-delivery system offers an improved release of the loaded imipenem antibiotic at the acidic infection site. Based on the high loading capacity and positive charge of the modified ZIF-8 nanoparticles, they are excellent carriers and are suitable for imipenem loading. The Imi@ZIF-8 nanosystem features synergistic antibacterial effects, combining ZIF-8 and imipenem to eliminate A. baumannii through different antibacterial mechanisms. When the loaded imipenem concentration reaches 20 µg/mL, Imi@ZIF-8 is highly effective against A. baumannii in vitro. Imi@ZIF-8 not only inhibits the biofilm formation of A. baumannii but also has a potent killing effect. Furthermore, in mice with celiac disease, the Imi@ZIF-8 nanosystem demonstrates excellent therapeutic efficacy against A. baumannii at imipenem concentrations of 10 mg/kg, and it can inhibit inflammatory reaction and local leukocyte infiltration. Due to its biocompatibility and biosafety, this nano-delivery system is a promising therapeutic strategy in the clinical treatment of A. baumannii infections, providing a new direction for the treatment of antibacterial infections.

Bcl-3 regulates the function of Th17 cells through raptor mediated glycolysis metabolism.

Bcl-3 is an atypical IκB family member that regulates transcription in the nucleus by binding to the p50/p52 homologous dimer subunit. Although various studies illustrate the important role of Bcl-3 in physiological function, its role in metabolism is still unclear. We found that Bcl-3 has a metabolic regulatory effect on autoimmunity. Bcl-3-depleted mice are unable to develop experimental autoimmune encephalomyelitis. The disease resistance was linked to an increase in lactate levels in Th17 cells, and lactate could alleviate EAE development in WT mice. Bcl-3 deficient mice had more differentiated Th17 cells and an increased extracellular acidification rate in these cells. Concurrently, their ultimate respiration rate and respiratory reserve capacity were significantly lower than wild-type mice. However, adding GNE-140 (LADH inhibitor) to Bcl-3-deficient Th17 cells could reverse the phenomenon, and lactate supplementation could increase the glycolysis metabolism of Th17 cells in WT mice. Mechanically, Bcl-3 could interact with Raptor through ANK and RNC domains. Therefore, Bcl-3 regulates Th17 pathogenicity by promoting Raptor mediated energy metabolism, revealing a novel regulation of adaptive immunity.