Abstract
Infections are a leading cause of mortality and morbidity in newborns. The high susceptibility of newborns to infection has been associated with a limited capacity to mount protective immune responses. Monocytes and macrophages are involved in the initiation, amplification, and termination of immune responses. Depending on cues received from their environment, monocytes differentiate into M1 or M2 macrophages with proinflammatory or anti-inflammatory and tissue repair properties, respectively. The purpose of this study was to characterize differences in monocyte to macrophage differentiation and polarization between newborns and adults. Monocytes from umbilical cord blood of healthy term newborns and from peripheral blood of adult healthy subjects were exposed to GM-CSF or M-CSF to induce M1 or M2 macrophages. Newborn monocytes differentiated into M1 and M2 macrophages with similar morphology and expression of differentiation/polarization markers as adult monocytes, with the exception of CD163 that was expressed at sevenfold higher levels in newborn compared to adult M1 macrophages. Upon TLR4 stimulation, newborn M1 macrophages produced threefold to sixfold lower levels of TNF than adult macrophages, while production of IL-1-β, IL-6, IL-8, IL-10, and IL-23 was at similar levels as in adults. Nuclear levels of IRF5, a transcription factor involved in M1 polarization, were markedly reduced in newborns, whereas the NF-κB and MAP kinase pathways were not altered. In line with a functional role for IRF5, adenoviral-mediated IRF5 overexpression in newborn M1 macrophages restored lipopolysaccharide-induced TNF production. Altogether, these data highlight a distinct immune response of newborn macrophages and identify IRF5 as a key regulator of macrophage TNF response in newborns.
Highlights
Despite advances in perinatal care, neonatal infections remain a leading cause of mortality and morbidity worldwide [1,2,3]
We report that in primary human monocytes exposed to granulocyte-macrophage colony-stimulating factor (GM-CSF), IRF5 was activated to a lower extent in newborns compared to adults during differentiation into M1 macrophages
The differentiation and polarization of freshly isolated newborn and adult monocytes into M1 and M2 macrophages following 7 days of culture with recombinant GM-CSF and M-CSF were analyzed by hematoxylin and eosin staining (Figure 1A) and by measuring the expression of maturation/differentiation markers by RT-PCR (CD14, CD64, SOCS2, SOCS3, and IRF4; Figure 1B) and flow cytometry (HLA-DR, CD80, CD163, CD206; Figure 1C)
Summary
Despite advances in perinatal care, neonatal infections remain a leading cause of mortality and morbidity worldwide [1,2,3]. Attempts at improving the outcome of neonatal sepsis through immune enhancing therapies including granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte transfusions, and intravenous immunoglobulins have only yielded a limited benefit [12,13,14]. This underscores our incomplete understanding of how newborns respond to infections, and the need for new therapeutic approaches
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