Salt transiently inhibits mitochondrial energetics in mononuclear phagocytes

BACKGROUND: Dietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially, but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional and functional adaption of human and murine mononuclear phagocytes (MNP). METHODS: Using Seahorse technology, pulsed stable isotope-resolved metabolomics and enzyme activity assays we characterize the central carbon metabolism and mitochondrial function of human and murine MNP under HS in vitro. HS as well as pharmacologic uncoupling of the electron transport chain (ETC) under normal salt (NS) is used to analyze mitochondrial function on immune cell activation and function (as determined by E.coli killing and CD4(+) T cell migration capacity). In two independent clinical studies we analyze the impact of a HS diet over two weeks (NCT02509962) and short-term salt challenge by a single meal (NCT04175249) on mitochondrial function of human monocytes in vivo. RESULTS: Extracellular sodium was taken up into the intracellular compartment followed by the inhibition of mitochondrial respiration in murine and human macrophages (MΦ). Mechanistically, HS reduces mitochondrial membrane potential, ETC complex II activity, oxygen consumption, and ATP production independently of the polarization status of MΦ. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like MΦ and diminished CD4(+) T cell migration in HS-treated M2-like MΦ. Pharmacologic uncoupling of the ETC under NS phenocopies HS-induced transcriptional changes and bactericidal function of human and murine MNP. Clinically, also in vivo rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both, a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of ̃x = 2mM and ̃x = 2.3mM, respectively, that correlated with decreased monocytic mitochondrial oxygen consumption. CONCLUSIONS: Our data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. While these functional changes might help to resolve bacterial infections, a shift towards pro-inflammation could accelerate inflammatory CVD

Synthesis and mechanical and tribological characterization of alumina-yttria stabilized zirconia (YSZ) nanocomposites with YSZ synthesized by means of an aqueous solution-gel. method or a hydrothermal route

In the present study, yttria stabilized zirconia (YSZ) nanoparticles, prepared by means of an aqueous solution–gel method or a hydrothermal route, are incorporated in a matrix of submicron alumina particles by wet mechanical milling. The microstructural characteristics and the mechanical and tribological properties of the obtained alumina–YSZ nanocomposites are evaluated as a function of different processing conditions like milling time, YSZ amount, sintering procedure and synthesis method of YSZ. It is noticed that the synthesis procedure and the agglomeration degree of the YSZ nanoparticles seriously affect the densification process of the alumina–YSZ nanocomposites and also their mechanical and tribological properties. The most probable cause for the difference is that the hydrothermally prepared YSZ nanoparticles are not as homogeneously distributed in the alumina matrix as the solution–gel prepared nanoparticles. Moreover the former nanoparticles have surface groups which release undesired gases during sintering. Thus to obtain a dense sample, nanocomposites with these nanoparticles require a higher sintering temperature and this has a negative effect on the mechanical and tribological properties of these materials.status: publishe