Heterogeneity of skin macrophages and the impact of high-salt diet in health and disease

Abstract

Excessive salt consumption, particularly from processed foods, is a growing health concern in Western countries, contributing to severe health consequences like cardiovascular disease and renal dysfunction. Beyond the known effects on the heart and kidneys, high-salt intake can also impact on our skin. Previous studies have shown that excess salt accumulates in skin connective tissue, influencing local cell behavior and activating immune cells, particularly macrophages and T cells. Macrophages are especially responsive to elevated salt levels, undergoing transcriptional and functional changes. <br/> In this study, we investigated how acute and chronic high-salt intake affects skin homeostasis and resident macrophages in mice. Chronic high-salt intake resulted in a skin phenotype reminiscent of psoriasis and atopic dermatitis, characterized by increased keratinocyte proliferation, epidermal thickening, elevated transepidermal water loss and reduced tissue hydration. We comprehensively profiled skin-resident macrophages, identifying five distinct subsets: Langerhans cells in the epidermis, as well as MHCII⁺ and MHCII^- blood vessel-associated macrophages, interstitial macrophages and nerve-associated macrophages in the dermis. These subsets differ in niche localization, surface marker expression, function and developmental origin. Their responses to high-salt conditions varied accordingly. Under homeostatic conditions, acute high-salt exposure led to increased macrophage abundances and broad changes in surface marker expression. Notably, all dermal macrophages showed a marked upregulation of CD32b, an inhibitory receptor involved in immune regulation. Blood vessel-associated macrophages were particularly affected, likely due to their proximity to the vasculature. These cells exhibited reduced volume and surface area and a shift towards a higher proportion of MHCII^- cells, which are more active in phagocytosis and efferocytosis than MHCII⁺ cells. <br/> While the most pronounced macrophage alterations occurred under acute high-salt conditions, a similar phenotype was observed in a model of allergic skin inflammation following chronic high-salt intake. Strikingly, CD32b upregulation was consistently observed across all dermal macrophage subsets, suggesting a potential compensatory role in response to both high-salt exposure and inflammation. In summary, chronic high-salt intake compromises skin integrity, while acute high-salt exposure drives broad phenotypic and functional changes in skin macrophages. These changes are amplified under inflammatory conditions. CD32b emerges as a central feature of macrophage adaptation in high-salt and inflammatory environments, presenting a promising target for future research.