Modulation of neonatal microbial recognition:: TLR-mediated innate immune responses are specifically and differentially modulated by human milk

被引:96
作者
LeBouder, Emmanuel
Rey-Nores, Julia E.
Raby, Anne-Catherine
Affolter, Michael
Vidal, Karine
Thornton, Catherine A.
Labeta, Mario O.
机构
[1] Cardiff Univ, Coll Med, Dept Med Biochem & Immunol, Cardiff CF14 4XX, Wales
[2] Univ Wales Inst, Sch Appl Sci, Cardiff, Wales
[3] Nestle Res Ctr, Dept Bioanalyt Sci, CH-1000 Lausanne, Switzerland
[4] Nestle Res Ctr, Dept Nutr & Hlth, CH-1000 Lausanne, Switzerland
[5] Univ Coll Swansea, Sch Med, Swansea, W Glam, Wales
基金
英国惠康基金;
关键词
D O I
10.4049/jimmunol.176.6.3742
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The mechanisms controlling innate microbial recognition in the neonatal gut are still to be fully understood. We have sought specific regulatory mechanisms operating in human breast milk relating to TLR-mediated microbial recognition. In this study, we report a specific and differential modulatory effect of early samples (days 1-5) of breast milk on ligand-induced cell stimulation via TLRs. Although a negative modulation was exerted on TLR2 and TLR3-mediated responses, those via TLR4 and TLR5 were enhanced. This effect was observed in human adult and fetal intestinal epithelial cell lines, monocytes, dendritic cells, and PBMC as well as neonatal blood. In the latter case, milk compensated for the low capacity of neonatal plasma to support responses to LPS. Cell stimulation via the IL-1R or TNFR was not modulated by milk. This, together with the differential effect on TLR activation, suggested that the primary effect of milk is exerted upstream of signaling proximal to TLR ligand recognition. The analysis of TLR4-mediated gene expression, used as a model system, showed that milk modulated TLR-related genes differently, including those coding for signal intermediates and regulators. A proteinaceous milk component of >= 80 kDa was found to be responsible for the effect on TLR4. Notably, infant milk formulations did not reproduce the modulatory activity of breast milk. Together, these findings reveal an unrecognized function of human milk, namely, its capacity to influence neonatal microbial recognition by modulating TLR-mediated responses specifically and differentially. This in turn suggests the existence of novel mechanisms regulating TLR activation.
引用
收藏
页码:3742 / 3752
页数:11
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