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 ␣ (IL-27R␣) Ϫ/Ϫ mice that lack a functional IL-27 receptor. Infected IL-27R␣ Ϫ/Ϫ pups also exhibited improved weight gain and reduced morbidity. This was consistent with reduced bacterial burdens and more efficient bacterial killing by Ly6B.2 ϩ 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.

HSP70-Homolog DnaK of Pseudomonas aeruginosa Increases the Production of IL-27 through Expression of EBI3 via TLR4-Dependent NF-κB and TLR4-Independent Akt Signaling

“…Consistent with this, a virulence factor of Bordetella pertussis upregulates expression of IL-10 in macrophages, thereby suppressing the development of cell-mediated immunity and limiting the clearance of invading pathogens [14]. Therefore, reduction in the IL-27 level promotes bacterial clearance, improves host response, and decreases mortality [15]. The plasma concentration of IL-27 is significantly elevated in murine models of sepsis, as well as in human patients with this condition; accordingly, it is considered to be a potential diagnostic marker for sepsis [16,17].…”

Early Mixed Inflammatory Response in Children with Sepsis

“…Combination with above the results of HLA-DR expression, this study implies that the therapeutic strategies at early stage in pediatric patient with sepsis should base on the effective treatment to proin ammatory reaction and suppressing the damage resulting from the immune response to infection. IL-27, as a new member of IL-12 family, plays duel-functions in the immune and in ammation reactions [10,29]. IL-27 exerts duel-regulation effects on Th1 cells [30].…”

“…As a member of IL-12 family of cytokines, IL-27 signals through a heterodimeric receptor complex consisting of the common IL-6 receptor chain gp130 and a unique IL-27 receptor α chain (IL-27R) WSX-1 [9]. By acting on various immune cells including T cells, B cells, macrophages and dendritic cells, IL-27 presents as pleiotropic cytokine in both pro-in ammatory and anti-in ammatory [10,11]. Studies has suggested that IL-27 could be a diagnostic biomarker for predicting bacterial infection in sepsis patients [12], and the blocking of IL-27 function could be used as a therapeutic strategy of sepsis [13,14].…”

IL-27 Regulation of Innate Immunity and Control of Microbial Growth

“…Similarly to macrophages, MDSCs have recently been found to be abundant producers of IL-27 in the spleen and blood of murine neonates [ 41 , 64 ]. MDSCs have potent immunosuppressive function and can be categorized into two subsets: monocytic or granulocytic.…”

“…Human CD66 + CD33 + C14 -/Lo MHC-II - granulocytic MDSCs also express IL-27 genes (U npublished data ). While initial research established MDSCs as key regulators of tumor micro-environments and cancer progression [ 81 ], recent studies have begun to elucidate the role of MDSC-derived IL-27 in neonatal immunity during infection [ 41 , 64 ]. MDSCs compromised macrophage control of bacterial growth during co-culture and this was partially dependent on IL-27 [ 41 ].…”