Abstract
Human neonates are highly susceptible to infection, which may be due in part to impaired innate immune function. Neonatal Toll-like receptor (TLR) responses are biased against the generation of pro-inflammatory/Th1-polarizing cytokines, yet the underlying mechanisms are incompletely defined. Here, we demonstrate that neonatal plasma polarizes TLR4-mediated cytokine production. When exposed to cord blood plasma, mononuclear cells (MCs) produced significantly lower TLR4-mediated IL-12p70 and higher IL-10 compared to MC exposed to adult plasma. Suppression by neonatal plasma of TLR4-mediated IL-12p70 production, but not induction of TLR4-mediated IL-10 production, was maintained up to the age of 1 month. Cord blood plasma conferred a similar pattern of MC cytokine responses to TLR3 and TLR8 agonists, demonstrating activity towards both MyD88-dependent and MyD88-independent agonists. The factor causing increased TLR4-mediated IL-10 production by cord blood plasma was heat-labile, lost after protein depletion and independent of lipoprotein binding protein (LBP) or soluble CD14 (sCD14). The factor causing inhibition of TLR4-mediated IL-12p70 production by cord blood plasma was resistant to heat inactivation or protein depletion and was independent of IL-10, vitamin D and prostaglandin E2. In conclusion, human neonatal plasma contains at least two distinct factors that suppress TLR4-mediated IL-12p70 production or induce IL-10 or production. Further identification of these factors will provide insight into the ontogeny of innate immune development and might identify novel targets for the prevention and treatment of neonatal infection.
Highlights
Toll-like receptors (TLRs) are key pathogen recognition receptors of the innate immune system that recognize highly conserved structures expressed by micro-organisms, called pathogen-associated molecular patterns (PAMPs) [1]
To determine whether decreased neonatal TLR4-mediated production of IL12p70 and increased production of IL-10 are due to differences in the cellular or soluble fraction of the blood, we isolated cord blood mononuclear cells (CBMCs) and adult peripheral blood mononuclear cells (PBMCs), resuspended them to equivalent concentrations (16106) and stimulated them with LPS in the presence of cord blood plasma or adult plasma (Fig. 1)
The source of plasma significantly influenced IL-10 production, with increased production in the presence of cord blood plasma by both CBMC and adult PBMC. These findings demonstrate that the differences in whole blood TLR4-mediated production of IL-12p70 and IL-10 between neonates and adults are due to differences in both the cellular and the soluble fraction of the blood
Summary
Toll-like receptors (TLRs) are key pathogen recognition receptors of the innate immune system that recognize highly conserved structures expressed by micro-organisms, called pathogen-associated molecular patterns (PAMPs) [1]. Birth imposes major challenges on the regulatory capacity of the immune system, including prevention of harmful allo-immune reactions to maternal antigens in utero, and balancing the transition from a sterile intra-uterine environment to the microbe-rich outside world [4]. To face these demands, neonatal TLR responses are physiologically biased against the production of pro-inflammatory cytokines [5,6,7]. Neonatal innate immune cells, including monocytes and dendritic cells (DC), demonstrate increased TLR-mediated production of certain cytokines (IL-10, IL-23) [9,10,11,12,13]. Insight into the mechanisms underlying this polarization is of great interest, as a biological phenomenon and to identify potential targets for the prevention and treatment of neonatal infections
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