Microbiota Signals during the Neonatal Period Forge Life-Long Immune Responses.

The microbiota regulates immunological development during early human life, with long-term effects on health and disease. Microbial products include short-chain fatty acids (SCFAs), formyl peptides (FPs), polysaccharide A (PSA), polyamines (PAs), sphingolipids (SLPs) and aryl hydrocarbon receptor (AhR) ligands. Anti-inflammatory SCFAs are produced by Actinobacteria, Bacteroidetes, Firmicutes, Spirochaetes and Verrucomicrobia by undigested-carbohydrate fermentation. Thus, fiber amount and type determine their occurrence. FPs bind receptors from the pattern recognition family, those from commensal bacteria induce a different response than those from pathogens. PSA is a capsular polysaccharide from B. fragilis stimulating immunoregulatory protein expression, promoting IL-2, STAT1 and STAT4 gene expression, affecting cytokine production and response modulation. PAs interact with neonatal immunity, contribute to gut maturation, modulate the gut-brain axis and regulate host immunity. SLPs are composed of a sphingoid attached to a fatty acid. Prokaryotic SLPs are mostly found in anaerobes. SLPs are involved in proliferation, apoptosis and immune regulation as signaling molecules. The AhR is a transcription factor regulating development, reproduction and metabolism. AhR binds many ligands due to its promiscuous binding site. It participates in immune tolerance, involving lymphocytes and antigen-presenting cells during early development in exposed humans.

Perinatal Infections With Ureaplasma.

Ureaplasma species are increasingly recognized as relevant pathogens in prenatal, perinatal and postnatal morbidity. They are commonly found as commensals on the mucous membranes of the lower urogenital tract of pregnant women, but when ascending, they can cause bacterial vaginosis, chorioamnionitis, premature birth and postnatal morbidities such as bronchopulmonary dysplasia, and early-onset neonatal sepsis and meningitis. The detection of Ureaplasma species is challenging and is not covered by routine diagnostics, and current empiric antibiotic treatment in neonates suspected of infection is not directed against Ureaplasma species. The aim of this review is to discuss the pathophysiology of Ureaplasma infections, the clinical consequences and the current difficulties in diagnosis and treatment by providing an overview of the current literature.

S100-Alarmins Are Essential Pilots of Postnatal Innate Immune Adaptation.

The restricted capacity of newborn infants to mount inflammatory responses toward microbial challenges has traditionally been linked to the high risk of septic diseases during the neonatal period. In recent years, substantial evidence has been provided that this characteristic of the neonatal immune system is actually a meaningful physiologic state that is based on specific transiently active cellular and molecular mechanisms and required for a favorable course of postnatal immune adaptation. The identification of physiologically high amounts of S100-alarmins in neonates has been one of the crucial pieces in the puzzle that contributed to the change of concept. In this context, innate immune immaturity could be redefined and assigned to the epigenetic silence of adult-like cell-autonomous regulation at the beginning of life. S100-alarmins represent an alternative age-specific mechanism of immune regulation that protects neonates from hyperinflammatory immune responses. Here, we summarize how infants are provided with S100-alarmins and why these allow an uneventful clash between the innate immune system and the extrauterine world. The mode of action of S100-alarmins is highlighted including their tuning functions at multiple levels for establishing a state of homeostasis with the environment in the newborn individual.

Contribution of ROS and metabolic status to neonatal and adult CD8+ T cell activation.

In neonatal T cells, a low response to infection contributes to a high incidence of morbidity and mortality of neonates. Here we have evaluated the impact of the cytoplasmic and mitochondrial levels of Reactive Oxygen Species of adult and neonatal CD8+ T cells on their activation potential. We have also constructed a logical model connecting metabolism and ROS with T cell signaling. Our model indicates the interplay between antigen recognition, ROS and metabolic status in T cell responses. This model displays alternative stable states corresponding to different cell fates, i.e. quiescent, activated and anergic states, depending on ROS levels. Stochastic simulations with this model further indicate that differences in ROS status at the cell population level contribute to the lower activation rate of neonatal, compared to adult, CD8+ T cells upon TCR engagement. These results are relevant for neonatal health care. Our model can serve to analyze the impact of metabolic shift during cancer in which, similar to neonatal cells, a high glycolytic rate and low concentrations of glutamine and arginine promote tumor tolerance.

Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.

Newborn infants have a high disposition to develop systemic inflammatory response syndromes (SIRSs) upon inflammatory or infectious challenges. Moreover, there is a considerable trafficking of hematopoietic cells to tissues already under noninflammatory conditions. These age-specific characteristics suggest a hitherto unappreciated crucial role of the vascular endothelium during the neonatal period. Here, we demonstrate that healthy neonates showed already strong endothelial baseline activation, which was mediated by a constitutively increased production of TNF-α. In mice, pharmacological inhibition of TNF-α directly after birth prevented subsequent fatal SIRS but completely abrogated the recruitment of leukocytes to sites of infection. Importantly, in healthy neonates, blocking TNF-α at birth disrupted the physiologic leukocyte trafficking, which resulted in persistently altered leukocyte profiles at barrier sites. Collectively, these data suggest that constitutive TNF-α-mediated sterile endothelial activation in newborn infants contributes to the increased risk of developing SIRS but is needed to ensure the postnatal recruitment of leukocytes to organs and interfaces.-Bickes, M. S., Pirr, S., Heinemann, A. S., Fehlhaber, B., Halle, S., Völlger, L., Willers, M., Richter, M., Böhne, C., Albrecht, M., Langer, M., Pfeifer, S., Jonigk, D., Vieten, G., Ure, B., von Kaisenberg, C., Förster, R., von Köckritz-Blickwede, M., Hansen, G., Viemann, D. Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.

Prenatal Maternal Depression and Neonatal Immune Responses.

OBJECTIVE: The aim of the study was to examine the association of lifetime maternal depression with regulation of immune responses in the infant, measured by cytokine levels and lymphocyte proliferation (LP) in cord blood mononuclear cells collected at delivery. METHODS: We studied women recruited in early pregnancy into the Project Viva longitudinal cohort who had cord blood assayed after delivery (N = 463). Women reported about depressive symptoms in midpregnancy (Edinburgh Postnatal Depression Scale) and depression history by questionnaire. Immune responses were assayed by an index of LP, and concentrations of five cytokines (interleukin [IL]-6, IL-10, IL-13, tumor necrosis tumor necrosis factor factor α, and interferon γ) after incubation of cord blood mononuclear cells either in medium alone or stimulated with phytohemagglutinin (PHA), cockroach extract, or house dust mite extract. We examined associations of maternal depression with these sets of cytokine measures using multivariable linear or tobit regression analyses. RESULTS: After adjustment for confounders (mother's age, race/ethnicity, education, household income, season of birth, and child sex), levels of IL-10 after stimulation with cockroach or dust mite allergen were lower in cord blood from ever versus never depressed women, and a similar trend was evident in IL-10 stimulated with PHA (percentage difference: cockroach extract = -41.4, p = .027; house dust mite extract = 1-36.0, p = .071; PHA = -24.2, p = .333). No significant differences were seen in levels of other cytokines or LP. CONCLUSIONS: Maternal depression is associated with offspring immune responses at birth, which may have implications for later life atopic risk or immune function.

Reduced internalization of TNF-ɑ/TNFR1 down-regulates caspase dependent phagocytosis induced cell death (PICD) in neonatal monocytes.

Phagocytosis-induced cell death (PICD) is diminished in cord blood monocytes (CBMO) as compared to cells from adults (PBMO) due to differences in the CD95-pathway. This may support a prolonged pro-inflammatory response with sequels of sustained inflammation as seen in neonatal sepsis. Here we hypothesized that TNF-α mediated induction of apoptosis is impaired in CBMO due to differences in the TNFR1-dependent internalization. Monocytes were infected with Escherichia coli-GFP (E. coli-GFP). Monocyte phenotype, phagocytic activity, induction of apoptosis, and TNF-α/TNF-receptor (TNFR) -expression were analysed. In the course of infection TNF-α-secretion of CBMO was reduced to 40% as compared to PBMO (p<0.05). Neutralization of TNF-α by an αTNF-α antibody reduced apoptotic PICD in PBMO four-fold (p < 0.05 vs. infection with E. coli). PICD in CBMO was reduced 5-fold compared to PBMO and showed less responsiveness to αTNF-α antibody. CBMO expressed less pro-apoptotic TNFR1, which, after administration of TNF-α or infection with E. coli was internalized to a lesser extent. With similar phagocytic capacity, reduced TNFR1 internalization in CBMO was accompanied by lower activation of caspase-8 (p < 0.05 vs. PBMO). Stronger caspase-8 activation in PBMO caused more activation of effector caspase-3 and apoptosis (all p < 0.05 vs. PBMO). Our results demonstrate that TNFR1 internalization is critical in mediating PICD in monocytes after infection with E.coli and is reduced in CBMO.

Impact of parental obesity on neonatal markers of inflammation and immune response.

BACKGROUND/OBJECTIVES: Maternal obesity may influence neonatal and childhood morbidities through increased inflammation and/or altered immune response. Less is known about paternal obesity. We hypothesized that excessive parental weight contributes to elevated inflammation and altered immunoglobulin (Ig) profiles in neonates. SUBJECTS/METHODS: In the Upstate KIDS Study maternal pre-pregnancy body mass index (BMI) was obtained from vital records and paternal BMI from maternal report. Biomarkers were measured from newborn dried blood spots (DBS) among neonates whose parents provided consent. Inflammatory scores were calculated by assigning one point for each of five pro-inflammatory biomarkers above the median and one point for an anti-inflammatory cytokine below the median. Linear regression models and generalized estimating equations were used to estimate mean differences (ß) and 95% confidence intervals (CI) in the inflammatory score and Ig levels by parental overweight/obesity status compared with normal weight. RESULTS: Among 2974 pregnancies, 51% were complicated by excessive maternal weight (BMI>25), 73% by excessive paternal weight and 28% by excessive gestational weight gain. Maternal BMI categories of overweight (BMI 25.0-29.9) and obese class II/III (BMI≥35) were associated with increased neonatal inflammation scores (ß=0.12, 95% CI: 0.02, 0.21; P=0.02 and ß=0.13, CI: -0.002, 0.26; P=0.05, respectively) but no increase was observed in the obese class I group (BMI 30-34.9). Mothers with class I and class II/III obesity had newborns with increased IgM levels (ß=0.11, CI: 0.04, 0.17; P=0.001 and ß=0.12, CI: 0.05, 0.19); P<0.001, respectively). Paternal groups of overweight, obese class I and obese class II/III had decreased neonatal IgM levels (ß=-0.08, CI: -0.13,-0.03, P=0.001; ß=-0.07, CI: -0.13, -0.01, P=0.029 and ß=-0.11, CI:-0.19,-0.04, P=0.003, respectively). CONCLUSIONS: Excessive maternal weight was generally associated with increased inflammation and IgM supporting previous observations of maternal obesity and immune dysregulation in offspring. The role of paternal obesity requires further study.

The functional biology of human milk oligosaccharides.

Human milk oligosaccharides (HMOs) are a group of complex sugars that are highly abundant in human milk, but currently not present in infant formula. More than a hundred different HMOs have been identified so far. The amount and composition of HMOs are highly variable between women, and each structurally defined HMO might have a distinct functionality. HMOs are not digested by the infant and serve as metabolic substrates for select microbes, contributing to shape the infant gut microbiome. HMOs act as soluble decoy receptors that block the attachment of viral, bacterial or protozoan parasite pathogens to epithelial cell surface sugars, which may help prevent infectious diseases in the gut and also the respiratory and urinary tracts. HMOs are also antimicrobials that act as bacteriostatic or bacteriocidal agents. In addition, HMOs alter host epithelial and immune cell responses with potential benefits for the neonate. The article reviews current knowledge as well as future challenges and opportunities related to the functional biology of HMOs.

Natural killer cell in the developing life.

\Natural killer (NK) cells that provide first-line innate immune reactions against virus-infected and tumor cells have different roles in different body sites and in different stages. From the beginning of life, NK cells participate in many aspects of development, especially in a successful pregnancy and a healthy neonatal stage. This article reviews recent advances regarding the role of NK cells in implantation, placentation and immune tolerance during pregnancy as well as in the neonatal immune defense. The interactions between NK cells and other immune cells in each developmental stage are discussed.

Immune responses in neonates.

Neonates have little immunological memory and a developing immune system, which increases their vulnerability to infectious agents. Recent advances in the understanding of neonatal immunity indicate that both innate and adaptive responses are dependent on precursor frequency of lymphocytes, antigenic dose and mode of exposure. Studies in neonatal mouse models and human umbilical cord blood cells demonstrate the capability of neonatal immune cells to produce immune responses similar to adults in some aspects but not others. This review focuses mainly on the developmental and functional mechanisms of the human neonatal immune system. In particular, the mechanism of innate and adaptive immunity and the role of neutrophils, antigen presenting cells, differences in subclasses of T lymphocytes (Th1, Th2, Tregs) and B cells are discussed. In addition, we have included the recent developments in the neonatal mouse immune system. Understanding neonatal immunity is essential to development of therapeutic vaccines to combat newly emerging infectious agents.

Inmunología perinatal / Perinatal immunology

Se ha considerado que el útero gestante es un lugar inmunológicamente privilegiado, donde el feto es protegido del rechazo por el sistema inmune materno, mediante un amplio repertorio de estrategias de evasión que contribuye a la sobrevivencia del feto. La gestación en sí misma constituye un acontecimiento de equilibrio inmunológico y la tolerancia inmunológica permite la progresión del embarazo, donde participan una secuencia sincronizada de eventos que se inicia desde la concepción y fertilización para dar lugar a la implantación y progresa hasta alcanzar un embarazo a término. El sistema inmune es la principal barrera que poseemos para protegernos de las infecciones. Durante la vida intrauterina, el feto está protegido por la madre de las agresiones externas, por lo que no necesita que su sistema inmunológico sea operativo, sin embargo, al nacer, recibe una avalancha de elementos extraños, por lo que necesitará disponer de cierta protección, así como una preparación para ejecutar las defensas necesarias para su protección inmunológica. La inmunidad sérica durante la vida fetal queda limitada a la transferencia a través de la placenta de IgG materna, a pesar de que el feto tiene la facultad de sintetizar inmunoglobulinas desde las primeras etapas de la gestación. Al nacimiento, el niño tiene su sistema inmunológico completo, aunque inmaduro, pero es capaz de responder a los estímulos antigénicos. Tiene múltiples anormalidades en el desarrollo de su sistema inmune, que involucran a los anticuerpos/inmunoglobulinas, complemento y granulocitos pudiendo contribuir a la alta incidencia de sus infecciones. El recién nacido carece de memoria inmunológica debido a que, en condiciones normales, el feto está exento de estímulos producidos por antígenos extraños. Dicha memoria se va adquiriendo a medida que entra en contacto con los diferentes antígenos. Se obtendrá cierta protección a las infecciones entéricas gracias a las IgA que aporta la lactancia materna. La exposición prenatal y postnatal a productos microbianos ambientales que pueden activar la inmunidad innata, puede acelerar el proceso de maduración del sistema inmune.(AU)

It has been considered the pregnant women`s womb as an immunological exceptional place, where fetus is protected against been rejected because of maternal immune system by means of a wide groups of evasive strategies that help in its survival. Pregnancy itself is an immunological equilibrium state and the immunological tolerance allow the progression of this event, where participate a synchronized sequence of biological events started from conception and fertilization to allow the implantation, and progress until to reach the pregnancy end. The immune system is our main barrier against infections. During intrauterine life fetus is protected by the mother against external aggressions, therefore he don`t need an operative immune system, nevertheless, at birth the new organisms receive an avalanche of strange elements needing some kind of protection as well as a preparation to carry out the necessary defense for his immunological protection. Serum immunity during fetal life is limited to the transference of maternal IgG through placenta, despite fetus capability to synthesize immunoglobulins from first stages of gestation. At birth the babe has a complete immunological system although immature but capable to respond to antigenic stimulus. He has multiples abnormalities in the immune system development that take account antibodies/immunoglobulin, complement and granulocytes contributing to his high incidence of infections. Newborn lack immunological memory because in normal conditions fetus is not stimulated by odd antigens. This memory is acquired through the contact with different antigens. It will be obtained some protection against enteric infections because IgA from maternal lactation. The prenatal and postnatal exposition to environmental microbial products that activate the innate immunity can accelerate the immune system maturing process.(AU)

Attenuation of respiratory syncytial virus-induced and RIG-I-dependent type I IFN responses in human neonates and very young children.

Newborn infants, including those born at term without congenital disorders, are at high risk of severe disease from respiratory syncytial virus (RSV) infection. Indeed, our current local surveillance data demonstrate that approximately half of children hospitalized with RSV were ≤3 mo old, and 74% were born at term. Informed by this clinical epidemiology, we investigated antiviral innate immune responses in early life, with the goal of identifying immunological factors underlying the susceptibility of infants and young children to severe viral lower respiratory tract infections. We compared RSV-induced innate cytokine production in blood mononuclear cells from neonates, young children aged 12-59 mo, and healthy adults. RSV-induced IFN-α production was primarily mediated by plasmacytoid dendritic cells (pDCs), and was significantly lower in term infants and young children < 5 y of age than in adults (p < 0.01). RSV-induced IFN-α production in human pDCs proceeded independently of endosomal TLRs, and human pDCs from healthy adult donors produced IFN-α in a retinoic acid-inducible gene I protein (RIG-I)-dependent manner. Of interest, young age and premature birth were independently associated with attenuated RIG-I-dependent IFN-α responses (p < 0.01). In contrast to IFN-α production, proinflammatory IL-6 responses to RSV were mediated by monocytes, appeared less dependent on RIG-I, and were significantly impaired only among preterm infants, not in term infants and young children. Our results suggest that human pDCs are less functional in early life, which may contribute to the increased susceptibility of infants and young children to severe RSV disease.

TLR3 impairment in human newborns.

Newborns are highly susceptible to viral infections. We hypothesized that this susceptibility could be due to a dysregulated expression of innate virus-sensing receptors, i.e., TLR3, TLR7, TLR8, and TLR9 and the cytosolic receptors retinoic acid-inducible gene I, melanoma differentiation-associated protein 5, protein kinase R, and IFN-γ-inducible protein 16. Cord blood mononuclear cells (CBMCs) expressed mRNA for all these receptors except for TLR3. In peripheral blood mononuclear cells (PBMCs), TLR3 mRNA was preferentially expressed in cytotoxic cells, particularly CD56(dim) NK cells. Cord NK cells in contrast showed low TLR3 mRNA expression and lacked TLR3 protein expression. Cord NK cells did not produce IFN-γ in response to polyinosinic-polycytidylic acid [poly(I:C)], whereas strong IFN-γ production was observed in poly(I:C)-stimulated adult NK cells. Cord NK cells had poor cytotoxic function that was only marginally enhanced by exposure to the TLR3 ligand poly(I:C). Opposite to NK cells from adults, their cytotoxicity was not improved by herpes simplex virus (HSV) exposure and they were unable to kill HSV-infected cells. There were no differences in the TLR3 mRNA levels among men, women, and pregnant women, implying that TLR3 is not under sex hormone control. However, decidual NK cells expressed low levels of TLR3 mRNA, which was attributed to their CD56(bright) phenotype. Our data show that cord blood NK cells have deficient TLR3 expression associated with an inability to respond to poly(I:C) and HSV activation and to kill HSV-infected cells. This might explain why newborns are particularly sensitive to neonatal HSV infections.

Prototypic long pentraxin PTX3 is present in breast milk, spreads in tissues, and protects neonate mice from Pseudomonas aeruginosa lung infection.

Newborns and infants present a higher susceptibility to infection than adults, a vulnerability associated with deficiencies in both the innate and adaptive immune systems. Innate immune receptors are sensors involved in the recognition and elimination of microbes that play a pivotal role at the interface between innate and adaptive immunity. Pentraxin 3 (PTX3), the prototypic long pentraxin, is a soluble pattern recognition receptor involved in the initiation of protective responses against selected pathogens. Because neonates are generally resistant to these pathogens, we suspected that PTX3 may be provided by a maternal source during the early life times. We observed that human colostrum contains high levels of PTX3, and that mammary epithelial cell and CD11b(+) milk cells constitutively produce PTX3. Interestingly, PTX3 given orally to neonate mice was rapidly distributed in different organs, and PTX3 ingested during lactation was detected in neonates. Finally, we observed that orally administered PTX3 provided protection against Pseudomonas aeruginosa lung infection in neonate mice. Therefore, breastfeeding constitutes, during the early life times, an important source of PTX3, which actively participates in the protection of neonates against infections. In addition, these results suggest that PTX3 might represent a therapeutic tool for treating neonatal infections and support the view that breastfeeding has beneficial effects on the neonates' health.

Longitudinal changes in CD4(+) T-cell memory responses induced by BCG vaccination of newborns.

BACKGROUND: Improved vaccination strategies against tuberculosis are needed, such as approaches to boost immunity induced by the current vaccine, BCG. Design of these strategies has been hampered by a lack of knowledge of the kinetics of the human host response induced by neonatal BCG vaccination. Furthermore, the functional and phenotypic attributes of BCG-induced long-lived memory T-cell responses remain unclear. METHODS: We assessed the longitudinal CD4 T-cell response following BCG vaccination of human newborns. The kinetics, function, and phenotype of these cells were measured using flow cytometric whole-blood assays. RESULTS: We showed that the BCG-specific CD4 T-cell response peaked 6-10 weeks after vaccination and gradually waned over the first year of life. Highly activated T-helper 1 cells, predominantly expressing interferon γ, tumor necrosis factor α, and/or interleukin 2, were present at the peak response. Following contraction, BCG-specific CD4 T cells expressed high levels of Bcl-2 and displayed a predominant CD45RACCR7 central memory phenotype. However, cytokine and cytotoxic marker expression by these cells was more characteristic of effector memory cells. CONCLUSIONS: Our findings suggest that boosting of BCG-primed CD4 T cells with heterologous tuberculosis vaccines may be best after 14 weeks of age, once an established memory response has developed.

Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells.

OBJECTIVE: Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors (OPRs) expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants. STUDY DESIGN: Using blood from preterm (≤ 30 weeks gestational age (GA), n=7) and full-term ( ≥ 37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1ß, IL-6, IL-8, IL-10, IL-12p70 and TNF-α), cyclic adenosine monophosphate (cAMP) levels and µ-, δ- and κ- opioid receptor (OPR) gene and protein expression, following in-vitro exposure to morphine, methadone, fentanyl or clonidine at increasing concentrations ranging from 0 to 1 mM. RESULT: Following lipopolysaccharide activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10(-5) M decreased all tested cytokines except IL-8. In contrast, clonidine at <10(-9) M increased IL-6, while at >10(-5) M increased IL-1ß and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three µ-, δ- and κ-OPR genes were expressed in mononuclear cells (MNC) from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10(-5)M decreased the expression of µ-OPR, but not δ- or κ-OPRs. CONCLUSION: Generalized cytokine suppression along with downregulation of µ-OPR expression observed in neonatal MNC exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.

Macrophage VLDL receptor promotes PAFAH secretion in mother's milk and suppresses systemic inflammation in nursing neonates.

Mother's milk is widely accepted as nutritious and protective to the newborn mammals by providing not only macronutrients but also immune-defensive factors. However, the mechanisms accounting for these benefits are not fully understood. Here we show that maternal very-low-density-lipoprotein (VLDL) receptor deletion in mice causes the production of defective milk containing diminished levels of platelet-activating factor acetylhydrolase (PAFAH). As a consequence, the nursing neonates suffer from alopecia, anaemia and growth retardation owing to elevated levels of pro-inflammatory platelet-activating factors. VLDL receptor deletion significantly impairs the expression of phospholipase A2 group 7 (Pla2g7) in macrophages, which decreases PAFAH secretion. Exogenous oral supplementation of neonates with PAFAH effectively rescues the toxicity. These findings not only reveal a novel role of VLDL receptor in suppressing inflammation by maintaining macrophage PAFAH secretion, but also identify the maternal VLDL receptor as a key genetic program that ensures milk quality and protects the newborns.

Innate immune activation in neonatal tracheal aspirates suggests endotoxin-driven inflammation.

BACKGROUND: Tracheal aspirates (TAs) from critically ill neonates accumulate bacterial endotoxin and demonstrate mobilization of endotoxin-binding proteins, but the potential bioactivity of endotoxin in TAs is unknown. We characterized innate immune activation in TAs of mechanically ventilated neonates. METHODS: Innate immune activation in TAs of mechanically ventilated neonates was characterized using a targeted 84-gene quantitative real-time (qRT) PCR array. Protein expression of cytokines was confirmed by multiplex assay. Expression and localization of the endotoxin-inducible antimicrobial protein Calgranulin C (S100A12) was assessed by flow cytometry. Endotoxin levels were measured in TA supernatants using the Limulus amoebocyte lysate assay. RESULTS: Analyses by qRT-PCR demonstrated expression of pattern recognition receptors, Toll-like receptor-nuclear factor κB and inflammasome pathways, cytokines/chemokines and their receptors, and anti-infective proteins in TA cells. Endotoxin positivity increased with postnatal age. As compared with endotoxin-negative TAs, endotoxin-positive TAs demonstrated significantly greater tumor necrosis factor (TNF), interleukin (IL)-6, IL-10, and serpin peptidase inhibitor, clade E, member 1 (SERPINE1) mRNA, and IL-10, TNF, and IL-1ß protein. Expression of S100A12 protein was localized to TA neutrophils. CONCLUSION: Correlation of endotoxin with TA inflammatory responses suggests endotoxin bioactivity and the possibility that endotoxin antagonists could mitigate pulmonary inflammation and its sequelae in this vulnerable population.