LPS Stimulation of Cord Blood Reveals a Newborn-Specific Neutrophil Transcriptomic Response and Cytokine Production

Mathias, Brittany; Mira, Juan C.; Rehfuss, Jonathan P.; Rincón, Jaimar; Ungaro, Ricardo; Nacionales, Dina C.; López, María Cecilia; Baker, Henry V.; Moldawer, Lyle L.; Larson, Shawn D.

doi:10.1097/shk.0000000000000800

Cited by 20 publications

(19 citation statements)

References 29 publications

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“…Neutrophils were captured from 350 μl of whole blood using positive selection with anti-CD66b monoclonal antibody, clone 80H3 (BioRad, Hercules, CA, USA) coated microfluidic devices as previously described and validated by Kotz et al , Warner et al and Mathias et al [8–10]. The microfluidic devices capture a fixed number of neutrophils, thus the total number of neutrophils captured were equivalent among groups regardless of any differences in total or differential counts.…”

Section: Methodsmentioning

confidence: 99%

Neutrophil chemotaxis and transcriptomics in term and preterm neonates

Raymond

Mathias

Murphy

et al. 2017

Translational Research

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Neutrophils play a crucial role in combating life-threatening bacterial infections in neonates. Previous studies investigating neonatal cell function have been limited because of restricted volume sampling. Here, using novel microfluidics approaches, we provide the first description of neutrophil chemotaxis and transcriptomics from whole blood of human term and preterm neonates, as well as young adults. Ex vivo percent cell migration, neutrophil velocity, and directionality to fMLP were measured from whole blood using time-lapse imaging of microfluidic chemotaxis. Genome-wide expression was also evaluated in CD66b+ cells using microfluidic capture devices. Neutrophils from preterm neonates migrated in fewer numbers compared to term neonates (preterm 12.3%, term 30.5%, p=0.008) and at a reduced velocity compared to young adults (preterm 10.1 μm/min, adult 12.7 μm/min, p=0.003). Despite fewer neutrophils migrating at slower velocities, neutrophil directionality from preterm neonates was comparable to adults and term neonates. 3,607 genes were differentially expressed among the three groups (p<0.001). Differences in gene expression between neutrophils from preterm and term neonates were consistent with reduced pathogen recognition and antimicrobial activity, but not neutrophil migration, by preterm neonates. In summary, preterm neonates have significant disturbances in neutrophil chemotaxis compared to term neonates and adults, and these differences in phenotype appear at the transcriptional level to target inflammatory pathways in general, rather than in neutrophil migration and chemotaxis.

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Section: Methodsmentioning

confidence: 99%

Neutrophil chemotaxis and transcriptomics in term and preterm neonates

Raymond

Mathias

Murphy

et al. 2017

Translational Research

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“…In this case, an early failure to control bacterial growth leads to rapid colonization of organs, cardiovascular failure, and death. Support for this latter hypothesis comes from genomic and functional studies on innate and adaptive immunity in neonates ( 25 , 31 ). It is likely, however, that both processes are active.…”

Section: Transcriptomic Response To Neonatal Sepsismentioning

confidence: 99%

Immunological Defects in Neonatal Sepsis and Potential Therapeutic Approaches

et al. 2017

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Despite advances in critical care medicine, neonatal sepsis remains a major cause of morbidity and mortality worldwide, with the greatest risk affecting very low birth weight, preterm neonates. The presentation of neonatal sepsis varies markedly from its presentation in adults, and there is no clear consensus definition of neonatal sepsis. Previous work has demonstrated that when neonates become septic, death can occur rapidly over a matter of hours or days and is generally associated with inflammation, organ injury, and respiratory failure. Studies of the transcriptomic response by neonates to infection and sepsis have led to unique insights into the early proinflammatory and host protective responses to sepsis. Paradoxically, this early inflammatory response in neonates, although lethal, is clearly less robust relative to children and adults. Similarly, the expression of genes involved in host protective immunity, particularly neutrophil function, is also markedly deficient. As a result, neonates have both a diminished inflammatory and protective immune response to infection which may explain their increased risk to infection, and their reduced ability to clear infections. Such studies imply that novel approaches unique to the neonate will be required for the development of both diagnostics and therapeutics in this high at-risk population.

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“…Thewhole genome transcriptomics revealed repression of genes involved in apoptosis, pathogen recognition, cytokine production, and antimicrobial activity in neonatal neutrophils as compared adult neutrophils, recapitulating the observational studies comparing neonatal and adult neutrophils. 20 These 17 and previous observations by the same group 21 suggest that defects in neutrophil migration may be just one component of a more generalized program of transcriptional repression involving genes directing inflammation and innate immunity.…”

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confidence: 62%