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.

西方饮食富含盐分，对健康构成各种威胁。高盐饮食（HSD）可以通过活化T细胞5（Nfat5）的信号转导途径刺激免疫，尤其是在钠储存的皮肤中。肾髓质也积聚钠以建立渗透梯度以节约用水。在这里，我们研究了HSD对尿路致病性大肠杆菌的免疫防御作用–诱发的肾盂肾炎，最常见的肾脏感染。出乎意料的是，在HSD的小鼠中，通过两种机制使肾盂肾炎加重。首先，在HSD中，必须排泄钠。因此，肾脏改用尿素来建立渗透梯度。然而，与钠相反，尿素抑制了中性粒细胞的抗菌功能，中性粒细胞是针对肾盂肾炎的主要免疫效应物。第二，人体通过抑制醛固酮合酶来降低盐皮质激素的产生，从而排泄钠。这导致了具有糖皮质激素功能的醛固酮前体的积累，从而消除了昼夜促肾上腺皮质激素驱动的糖皮质激素的节律，并全身性地损害了中性粒细胞的发育和抗菌功能。始终如一地，在HSD下单核细胞增生李斯特菌感染也以糖皮质激素依赖性方式加剧。糖皮质激素直接诱导Nfat5表达，但肾脏Nfat5表达的药理正常化未能恢复抗菌防御。最后，食用HSD 1周的健康人表现出糖皮质激素过多和抗菌素中性粒细胞功能受损。总之，HSD通过改变局部微环境并通过糖皮质激素介导的免疫抑制作用来独立抑制肾内中性粒细胞Nfat5。这些发现反对细菌感染期间高盐的摄入。