Innate immunity and sepsis

Our research aims to enhance the understanding of innate immune defense mechanisms against infection and the pathogenesis and pathobiology of sepsis. Innate immunity is grounded in the concept of sensing danger signals—such as microbes, toxins, and endogenous molecules released by damaged or dying cells—through germ-line encoded pattern recognition receptors. Over the years, we have investigated how pathogen-associated molecular patterns, such as lipopolysaccharide (LPS, endotoxin), are recognized by pattern recognition molecules and receptors, including LPS-binding protein, CD14, and Toll-like receptors. Cytokines are essential mediators of the innate immune system, orchestrating the cellular and humoral responses necessary to eliminate or contain invading pathogens. One such mediator is macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine that bridges innate and adaptive immune responses. MIF is expressed by innate immune cells—such as monocytes, macrophages, neutrophils, and dendritic cells—in response to stress, danger signals, and neuroendocrine stimuli. It activates cells by binding to a multicomponent receptor comprising CD74, CD44, CXCR2, and CXCR4. MIF modulates inflammatory, infectious, and autoimmune diseases, notably as a counter-regulator of glucocorticoids, and influences processes such as cell proliferation, survival, and migration.

The regulation of the host inflammatory response is a delicate balance. Dysregulated innate immune responses—whether insufficient or excessive—can have severe consequences for the host, as exemplified in sepsis. Thus, tight control of innate immunity is crucial for managing microbial invasion, responding appropriately to danger signals, and ensuring a return to homeostasis.

1. CD44-mediated regulation of dendritic cell migration by macrophage migration inhibitory factor (MIF).
2. Personalized immunotherapy in sepsis (multicenter and multinational, double-blind, double-dummy randomized clinical trial).
3. Safety and efficacy of recombinant interferon-gamma 1b (rIFN-gamma 1b) given with standard therapy in patients with candidemia.