Interleukin-17D Aggravates Sepsis by Inhibiting Macrophage Phagocytosis

Interleukin-17D has been shown to participate in the control of viral infections and cancer. Here we hypothesized that interleukin-17D may play a potential role in sepsis.Prospective randomized animal investigation and in vitro human blood studies.Research laboratory from a university hospital.Female C57BL/6J mice, sepsis patients by Sepsis-3 definitions, ICU patient controls, and healthy individuals.Serum concentrations of interleukin-17D were measured and analyzed in human sepsis patients, patient controls, and healthy individuals. The contribution of interleukin-17D to sepsis-related survival, bacterial burden, and organ injury was assessed in a murine model of cecal ligation and puncture-induced polymicrobial sepsis by the use of anti-interleukin-17D antibody and recombinant interleukin-17D protein. The effects of interleukin-17D on bacterial phagocytosis by macrophages were also investigated using in vitro cell models.On the day of ICU admission (day 0), septic patients had significantly higher serum concentrations of interleukin-17D than patient controls and healthy individuals. Serum interleukin-17D levels remained significantly elevated in septic patients from ICU admission to day 3 and correlated with Sequential (Sepsis-related) Organ Failure Assessment scores and documented bacteremia on day 0. Furthermore, nonsurvivors of septic patients displayed significantly higher interleukin-17D levels compared with survivors of septic patients on days 0 and 1 of ICU admission. In animal models of sepsis, treatment with anti-interleukin-17D antibody protected mice from cecal ligation and puncture-induced severe sepsis, which was associated with improved bacterial clearance and organ injury. Conversely, administration of recombinant interleukin-17D protein aggravated cecal ligation and puncture-induced nonsevere sepsis. Furthermore, we found that interleukin-17D impaired bacterial phagocytosis by macrophages. Phagocytosis inhibition by interleukin-17D involved its ability to down-regulate the activation of nuclear factor-κB signaling pathway in macrophages upon bacterial infection.This study indicates a previously undescribed role of interleukin-17D in sepsis and identifies a new target for antisepsis treatment.