Inflammatory Ly6Chigh Monocytes Protect against Candidiasis through IL-15-Driven NK Cell/Neutrophil Activation

Abstract

Neutrophils play a crucial role in defense against systemic candidiasis, a disease associated with a high mortality rate in patients receiving immunosuppressive therapy, although the early immune mechanisms that boost the candidacidal activity of neutrophils remain to be defined in depth. Here, we used a murine model of systemic candidiasis to explore the role of inflammatory Ly6C monocytes in NK cell-mediated neutrophil activation during the innate immune response against C. albicans. We found that efficient anti-Candida immunity required a collaborative response between the spleen and kidney, which relied on type I interferon-dependent IL-15 production by spleen inflammatory Ly6C monocytes to drive efficient activation and GM-CSF release by spleen NK cells; this in turn was necessary to boost the Candida killing potential of kidney neutrophils. Our findings unveil a role for IL-15 as a critical mediator in defense against systemic candidiasis and hold promise for the design of IL-15-based antifungal immunotherapies.

Post-sepsis immunosuppression depends on NKT cell regulation of mTOR/IFN-γ in NK cells

“…LPS. We compared Ly6c + inflammatory macrophages, a key part of the clearance of primary Candida infection (16,17), with Ly6cmacrophages ( Figure 1D). Given the susceptibility to secondary candidemia at earlier time points (day 1 and day 3 of endotoxemia; Figure 1B), we focused on gene clus- 19) or later development of secondary Candida infection (n = 12).…”

Long-term reprogramming of the innate immune system

“…The process of monocyte differentiation into macrophages is also associated with rewiring of cellular metabolism. Activated proinflammatory macrophages consume large quantities of glucose in order to fuel glycolysis and OXPHOS, both necessary to produce great amounts of proinflammatory cytokines and reactive oxygen species (ROS) . Conversely, the metabolism of antiinflammatory macrophages is mainly mitochondrial and characterized by a blockade of glycolysis .…”

Fungal symbionts produce prostaglandin E2to promote their intestinal colonization

“…Since intestinal macrophages limit fungal colonization of the gut [15] and tissue-resident phagocytes are required for control of fungal infection in various tissues [28, 42, 43], we postulated that fungal PGE 2 might potentiate fungal fitness by acting on the fungi themselves and/or host tissular phagocytes to improve the ability of C. albicans to evade killing by phagocytes. To elucidate the relationship between fungal PGE 2 , tissular phagocytes, and fungal fitness in the host, we assessed the competitive fitness of the WT and ole2/ole2 strains in mice depleted of phagocytes.…”