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Elevated Levels of Interleukin-27 in Early Life Compromise Protective Immunity in a Mouse Model of Gram-Negative Neonatal Sepsis.

Abstract：

:Neonates are at increased risk for bacterial sepsis. We established that the immune-suppressive cytokine interleukin-27 (IL-27) is elevated in neonatal mice. Similarly, human cord blood-derived macrophages express IL-27 genes and secrete more cytokine than macrophages from adults. In the present work, we hypothesized that increased levels of IL-27 predispose neonatal mice to more severe infection during Gram-negative sepsis. Serum IL-27 levels continued to rise during infection. Peripheral tissue analysis revealed systemic IL-27 expression, while myeloid cell profiling identified Gr-1- and F4/80-expressing cells as the most abundant producers of IL-27 during infection. Increased IL-27 levels were consistent with increased mortality that was improved in IL-27 receptor α (IL-27Rα)-/- mice that lack a functional IL-27 receptor. Infected IL-27Rα-/- pups also exhibited improved weight gain and reduced morbidity. This was consistent with reduced bacterial burdens and more efficient bacterial killing by Ly6B.2+ myeloid cells and macrophages compared to WT neonates. Live animal imaging further supported a more severe and disseminated infection in WT neonates. This is the first report to describe the impact of elevated early-life IL-27 on the host response in a neonatal infection model while also defining the cell and tissue sources of cytokine. IL-27 is frequently associated with suppressed inflammation. In contrast, our findings demonstrate that IL-27 indirectly promotes an inflammatory cytokine response during neonatal sepsis by directly compromising control of bacteria that drive the inflammatory response. Collectively, our results suggest that IL-27 represents a therapeutic target to limit susceptibility and improve infectious outcomes in neonatal sepsis.

journal_name

Infect Immun

journal_title

Infection and immunity

authors

Seman BG,Vance JK,Rawson TW,Witt MR,Huckaby AB,Povroznik JM,Bradford SD,Barbier M,Robinson CM

doi

10.1128/IAI.00828-19

subject

Has Abstract

pub_date

2020-02-20 00:00:00

issue

eissn

0019-9567

issn

1098-5522

pii

IAI.00828-19

journal_volume

pub_type

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Elevated Levels of Interleukin-27 in Early Life Compromise Protective Immunity in a Mouse Model of Gram-Negative Neonatal Sepsis.