A high salt diet (HSD) has been reported to promote inflammation, anti-infectious immunity but also autoimmunity, suggesting that it may drive a distinct type of metaflammation. The sodium-sensitive transcription factor Nfat5 mediates certain aspects of the HSD-induced immunostimulation, yet there are Nfat5-independent pathways that are little understood. We have observed that feeding mice a HSD aggravated a model of pyelonephritis, one of the most prevalent bacterial infections. The underlying mechanism involved suppressed neutrophil development and effector functions by HSD-induced elevation of intrarenal urea and systemic glucocorticoid levels, but this was independent of Nfat5. In Aim 1 of this proposal, we will study the underlying cell and molecular biological mechanisms, including effects of HSD-induced mediators on neutrophil phagocytosis, phagosome maturation, antibacterial effector functions and metabolism. In Aim 2, we will study whether the HSD-induced mechanisms suppress a neutrophil-mediated model of crescentic glomerulonephritis (cGN), namely ANCA-associated vasculitis, a rapidly progressing potentially fatal disease affecting the kidney and lung. In both Aims 1 and 2, we will clarify the role of Nfat5 by using specific antisense oligonucleotides and using mice in which neutrophils or macrophages lack this factor. In Aim 3, we will utilise the Rhineland study to analyse on the population level, whether a HSD is epidemiologically connected with the incidences of bacterial infections or vasculitis.