Sepsis is a severe life-threatening multi-organ disorder stemming from the host's dysfunctional response against microbial invasion [1]. The immunosuppressive state of sepsis is closely related to the decreased number and activity of phagocytes [2], [3], [4]. Macrophages, derived from monocytes, are important phagocytes that play a central role in orchestrating innate immune responses, including phagocytosis of pathogens and elimination of damaged cells during sepsis. These responses are not only essential for the elimination of infection but also for the prevention of life-threatening multi-organ disorder in the course of sepsis [4]. Enhancing bacterial phagocytosis by macrophages and eliminating invading pathogens is a big deal in current research on sepsis prevention and treatment [5], [6].

Recently, extracellular histones have been identified as important mediators of sepsis, acting as damage-associated molecular patterns that influence cytotoxicity and further affect the innate immune system [7], [8], [9], [10], [11]. Elevated circulating histone levels have been discovered to have a positive correlation with mortality in septic patients [7]. Furthermore, histone-stimulated mice have pathophysiological features mimicking sepsis, including the damage of various types of cells, the procoagulant response, and immune abnormalities [7], [8], [9], [10], [11]. Among multiple inflammatory diseases, extracellular histones stimulate macrophage-mediated excessive inflammatory responses in different organ tissues [11], [12], [13], [14]. However, no reports indicate whether histones affect survival and bacterial phagocytosis in macrophages during sepsis.

Studies have revealed that the normal function of immune cells is intimately linked to the nutrition in their microenvironment [15], [16]. Magnesium (Mg2+) is an essential nutrient that serves as a Ca2+ antagonist to preserve homeostasis in the body through more than 300 biochemical reactions [17], [18]. It is largely feasible to take advantage of Mg2+ for its salutary and bioactive anti-inflammatory, antioxidant, and anti-aging properties [19], [20], but it is its effects on immune aspects that caught our attention [15], [21]. Basic research substantiates the protective effect of Mg2+ on cardiotoxicity, lung injury, and liver injury in sepsis, but whether it has a protective role in histone-induced macrophage damage remains unknown [20], [22], [23], [24].

In this study, we aimed to investigate the “Mg2+–extracellular histone–macrophage” relationship, using clinical data and basic experiments to explore whether histones affect survival and bacterial phagocytosis in macrophages, as well as to further assess whether Mg2+ has a protective effect on histone-mediated macrophage damage and its possible molecular mechanisms.