The Functional Role of CD169+ Macrophages in Septic Shock

Abstract

Abstract Sepsis affects more than 30 million people and accounts for approximately 6 million deaths worldwide each year. Sepsis is often associated with gram-positive, gram-negative, or fungal infections. Currently, there are no known cures for sepsis; however, current therapeutic strategies consist of supportive care to keep vital organs functional and antibiotics to combat infections, with survival prognosis contingent on early detection. Our current knowledge of the cellular and molecular mechanisms that regulate the inflammatory pathways resulting in sepsis is limited. Notably, we know little about the precise subpopulations of immune cells that play a central role during sepsis. Here we examined the specific role of CD169+ macrophages and its immunological receptors in septic shock. We utilized the CD169-DTR mouse to selectively and temporally deplete CD169+ macrophages. Using this model, we examined survival, cytokine/chemokine milieu, and cellularity in response to gram-negative LPS. We report the critical role of CD169+ macrophages and the CD169 receptor in protection against LPS induced septic shock. We show that in the absence of these macrophages, mice stimulated with sublethal LPS fail to survive and exhibit increased inflammatory cytokines and impaired IL-10 production. Protection against LPS induced lethality is rescued by supplemental treatment with recombinant IL-10. Lastly, we show that following LPS treatment, CD169+ macrophages are the initial targeted cell. These findings not only reveal a pivotal role for CD169+ macrophages but also the role for the CD169 receptor as a critical mediator of protection from sepsis induced lethality, and provide new therapeutic targets against sepsis.