RT Journal Article SR Electronic T1 A high-salt diet compromises antibacterial neutrophil responses through hormonal perturbation JF Science Translational Medicine FD American Association for the Advancement of Science SP eaay3850 DO 10.1126/scitranslmed.aay3850 VO 12 IS 536 A1 Jobin, Katarzyna A1 Stumpf, Natascha E. A1 Schwab, Sebastian A1 Eichler, Melanie A1 Neubert, Patrick A1 Rauh, Manfred A1 Adamowski, Marek A1 Babyak, Olena A1 Hinze, Daniel A1 Sivalingam, Sugirthan A1 Weisheit, Christina A1 Hochheiser, Katharina A1 Schmidt, Susanne V. A1 Meissner, Mirjam A1 Garbi, Natalio A1 Abdullah, Zeinab A1 Wenzel, Ulrich A1 Hölzel, Michael A1 Jantsch, Jonathan A1 Kurts, Christian YR 2020 UL http://stm.sciencemag.org/content/12/536/eaay3850.abstract AB Sodium chloride (salt) has been shown to invigorate immune responses in various contexts. In contrast, Jobin et al. now show that salt can impair neutrophil antibacterial responses. Mice on a high-salt diet experienced exacerbated E. coli kidney or systemic Listeria monocytogenes infections due to reduced capacity of neutrophils to kill ingested bacteria. The neutrophil deficiencies were not due directly to salt or urea but instead were dependent on salt-induced hyperglucocorticoidism. In addition, neutrophils from healthy volunteers were less capable of controlling bacteria ex vivo after consumption of a high-salt diet. Given that the typical Western diet is replete with salt, these findings reveal that people might be making themselves more vulnerable to bacterial infections.The Western diet is rich in salt, which poses various health risks. A high-salt diet (HSD) can stimulate immunity through the nuclear factor of activated T cells 5 (Nfat5)–signaling pathway, especially in the skin, where sodium is stored. The kidney medulla also accumulates sodium to build an osmotic gradient for water conservation. Here, we studied the effect of an HSD on the immune defense against uropathogenic E. coli–induced pyelonephritis, the most common kidney infection. Unexpectedly, pyelonephritis was aggravated in mice on an HSD by two mechanisms. First, on an HSD, sodium must be excreted; therefore, the kidney used urea instead to build the osmotic gradient. However, in contrast to sodium, urea suppressed the antibacterial functionality of neutrophils, the principal immune effectors against pyelonephritis. Second, the body excretes sodium by lowering mineralocorticoid production via suppressing aldosterone synthase. This caused an accumulation of aldosterone precursors with glucocorticoid functionality, which abolished the diurnal adrenocorticotropic hormone–driven glucocorticoid rhythm and compromised neutrophil development and antibacterial functionality systemically. Consistently, under an HSD, systemic Listeria monocytogenes infection was also aggravated in a glucocorticoid-dependent manner. Glucocorticoids directly induced Nfat5 expression, but pharmacological normalization of renal Nfat5 expression failed to restore the antibacterial defense. Last, healthy humans consuming an HSD for 1 week showed hyperglucocorticoidism and impaired antibacterial neutrophil function. In summary, an HSD suppresses intrarenal neutrophils Nfat5-independently by altering the local microenvironment and systemically by glucocorticoid-mediated immunosuppression. These findings argue against high-salt consumption during bacterial infections.