Abstract
BackgroundPatients experiencing large thermal injuries are susceptible to opportunistic infections that can delay recovery and lead to sepsis. Dendritic cells (DC) are important for the detection of pathogens and activation of the innate and acquired immune responses. DCs are significantly decreased in burn patients early after injury, and the development of sepsis is associated with persistent DC depletion. In a murine model of burn wound infection, the enhancement of DCs after injury by treatment with the DC growth factor Fms-like tyrosine kinase-3 ligand (FL) enhances neutrophil migration to infection, improves bacterial clearance, and increases survival in a DC-dependent manner. FL expands the production of both conventional DCs (cDC) and plasmacytoid DCs (pDC). It has been established that cDCs are required for some of the protective effects of FL after burn injury. This study was designed to determine the contribution of the pDC subset.MethodsMice were subjected to full-thickness scald burns under deep anesthesia and were provided analgesia. pDCs were depleted by injection of anti-plasmacytoid dendritic cell antigen-1 antibodies. Survival, bacterial clearance, and neutrophil responses in vivo and in vitro were measured.ResultsDepletion of preexisting pDCs, but not FL-expanded pDCs, abrogated the beneficial effects of FL on survival, bacterial clearance, and neutrophil migration in response to burn wound infection. This requisite role of pDCs for FL-mediated enhancement of neutrophil migratory capacity is not due to direct effects of pDCs on neutrophils. cDCs, but not pDCs, directly increased neutrophil migratory capacity after co-culture.ConclusionsThe protective effects of FL treatment after burn injury are mediated by both pDCs and cDCs. Pharmacological enhancement of both DC subtypes by FL is a potential therapeutic intervention to enhance immune responses to infection and improve outcome after burn injury.
Highlights
Patients experiencing large thermal injuries are susceptible to opportunistic infections that can delay recovery and lead to sepsis
Fms-like tyrosine kinase-3 ligand (FL)-mediated resistance to burn wound infection is dependent upon the presence of plasmacytoid Dendritic cells (DCs) (pDC) during treatment As previously reported [8], treatment of mice with FL after burn injury significantly improved survival following a lethal P. aeruginosa burn wound infection
Survival in mice depleted of pDCs after FL treatment, during wound infection, was 65% and similar to that in FL-treated control mice
Summary
Patients experiencing large thermal injuries are susceptible to opportunistic infections that can delay recovery and lead to sepsis. DCs are significantly decreased in burn patients early after injury, and the development of sepsis is associated with persistent DC depletion. Patients experiencing large thermal injuries are susceptible to opportunistic infections, sepsis, and associated complications. Despite the widespread use of antibiotics, infection remains the leading cause of death among severely burned patients, necessitating the need of immune-modulating therapies [1]. Burn patients have a significant decrease in circulating DCs early after injury and development of sepsis is associated with persistent DC depletion over the first 2 weeks after injury [7]. Restoration of DC numbers and functions after burn injury may restore appropriate immune responses and prevent burn-associated infections
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