An Impaired Inflammatory Cytokine Response to Gram-Negative LPS in Human Neonates is Associated with the Defective TLR-Mediated Signaling Pathway

Li, Yi Ping; Sheng, Yu; Huang, Zhi Hong; Huang, Jie; Pan, Jian; Feng, Xing; Zhang, Xue Guang; Wang, Jiang Huai; Wang, Jian

doi:10.1007/s10875-015-0128-6

Cited by 20 publications

(12 citation statements)

References 37 publications

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“…We have found equivalent levels of surface expression of TLR4 between HC and TRAPS, suggesting that the LPS-hyperresponsiveness observed was not mediated by differences in TLR4 surface expression. Interestingly, TNFR1 knockout mice are resistant to LPS-induced shock, and human monocytes that are deficient in TLR4 are also resistant to LPS ( 6 , 38 ). Thus, mutant TNFR1 may act in synergy with the TLR4 signaling pathway, triggering increased cellular stress, and consequent lowering of the activation threshold for TLR4-LPS signaling which, in turn, further augments intracellular stress levels in DF with T50M, C472, and C88R mutations in TNFRSF1A .…”

Section: Discussionmentioning

confidence: 99%

Inositol-Requiring Enzyme 1-Mediated Downregulation of MicroRNA (miR)-146a and miR-155 in Primary Dermal Fibroblasts across Three TNFRSF1A Mutations Results in Hyperresponsiveness to Lipopolysaccharide

et al. 2018

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Tumor necrosis factor (TNF)-receptor-associated periodic fever syndrome (TRAPS) is a rare monogenic autoinflammatory disorder characterized by mutations in the TNFRSF1A gene, causing TNF-receptor 1 (TNFR1) misfolding, increased cellular stress, activation of the unfolded protein response (UPR), and hyperresponsiveness to lipopolysaccharide (LPS). Both microRNA (miR)-146a and miR-155 provide negative feedback for LPS-toll-like receptor 2/4 signaling and cytokine production, through regulation of nuclear factor kappa B (NF-κB). In this study, we hypothesized that proinflammatory cytokine signaling in TRAPS downregulates these two miRs, resulting in LPS-induced hyperresponsiveness in TRAPS dermal fibroblasts (DFs), irrespective of the underlying genetic mutation. Primary DF were isolated from skin biopsies of TRAPS patients and healthy controls (HC). TNFR1 cell surface expression was measured using immunofluorescence. DF were stimulated with LPS, interleukin (IL)-1β, thapsigargin, or TNF, with and without inositol-requiring enzyme 1 (IRE1) inhibitor (4u8C), following which miR-146a and miR-155 expression was measured by RT-qPCR. IL-1β, IL-6, and TNF secretion was measured by enzyme-linked immunosorbent assays, and baseline expression of 384 different miRs was assessed using microfluidics assays. TNFR1 was found to be expressed on the surface of HC DF but expression was deficient in all samples with TRAPS-associated mutations. HC DF showed significant dose-dependent increases in both miR-146a and miR-155 expression levels in response to LPS; however, TRAPS DF failed to upregulate either miR-146a or miR-155 under the same conditions. This lack of miR-146a and miR-155 upregulation was associated with increased proinflammatory cytokine production in TRAPS DF in response to LPS challenge, which was abrogated by 4u8C. Incubation of HC DF with IL-1β led to downregulation of miR-146a and miR-155 expression, which was dependent on IRE1 enzyme. We observed global dysregulation of hundreds of other miRs at baseline in the TRAPS DF. In summary, these data suggest a mechanism whereby IL-1β, produced in response to activation of the UPR in TRAPS DF, downregulates miR-146a and miR-155, by inducing IRE1-dependent cleavage of both these miRs, thereby impairing negative regulation of NF-κB and increasing proinflammatory cytokine production.

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Section: Discussionmentioning

confidence: 99%

Inositol-Requiring Enzyme 1-Mediated Downregulation of MicroRNA (miR)-146a and miR-155 in Primary Dermal Fibroblasts across Three TNFRSF1A Mutations Results in Hyperresponsiveness to Lipopolysaccharide

et al. 2018

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“…Neonatal monocytes also have reduced levels of major histocompatibility complex (MHC) class II expression on their surface, resulting in a diminished capacity for antigen presentation (47). Toll-like receptor (TLR)-mediated signal transduction pathways are also impaired in neonatal monocytes, resulting in the reduced activation of NF-B, which is an important transcription factor involved in immune response regulation (48).…”

Section: Innate Immunity Deficienciesmentioning

confidence: 99%

Intrinsic Maturational Neonatal Immune Deficiencies and Susceptibility to Group B Streptococcus Infection

2017

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Although a normal member of the gastrointestinal and vaginal microbiota, group B (GBS) can also occasionally be the cause of highly invasive neonatal disease and is an emerging pathogen in both elderly and immunocompromised adults. Neonatal GBS infections are typically transmitted from mother to baby either or during passage through the birth canal and can lead to pneumonia, sepsis, and meningitis within the first few months of life. Compared to the adult immune system, the neonatal immune system has a number of deficiencies, making neonates more susceptible to infection. Recognition of GBS by the host immune system triggers an inflammatory response to clear the pathogen. However, GBS has developed several mechanisms to evade the host immune response. A comprehensive understanding of this interplay between GBS and the host immune system will aid in the development of new preventative measures and therapeutics.

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“…9 While cytokine levels in late pregnancy 10 or in newborns born by CD 11 have been studied, reports on the effects of other obstetric factors on the function of the immune system later are rare. 9 While cytokine levels in late pregnancy 10 or in newborns born by CD 11 have been studied, reports on the effects of other obstetric factors on the function of the immune system later are rare.…”

Section: Introductionmentioning

confidence: 99%

“…The ability of TLRs to activate antigen-presenting cells and thus stimulate the synthesis and excretion of a broad range of molecules, including cytokines, is vital to the initiation of adaptive immune response. 9 While cytokine levels in late pregnancy 10 or in newborns born by CD 11 have been studied, reports on the effects of other obstetric factors on the function of the immune system later are rare.…”

Section: Introductionmentioning

confidence: 99%

The lack of natural processes of delivery and neonatal intensive care treatment lead to impaired cytokine responses later in life

Martikainen

Keski‐Nisula

Jakupović

et al. 2017

Am J Reprod Immunol

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An Impaired Inflammatory Cytokine Response to Gram-Negative LPS in Human Neonates is Associated with the Defective TLR-Mediated Signaling Pathway

Abstract: These results indicate that in contrast to the adult, human neonates display deficiencies in innate immunity-associated inflammatory cytokine responses due to their defective TLR signaling pathways, which may render them more susceptible to microbial infection.

Cited by 20 publications

References 37 publications

Inositol-Requiring Enzyme 1-Mediated Downregulation of MicroRNA (miR)-146a and miR-155 in Primary Dermal Fibroblasts across Three TNFRSF1A Mutations Results in Hyperresponsiveness to Lipopolysaccharide

Inositol-Requiring Enzyme 1-Mediated Downregulation of MicroRNA (miR)-146a and miR-155 in Primary Dermal Fibroblasts across Three TNFRSF1A Mutations Results in Hyperresponsiveness to Lipopolysaccharide

Intrinsic Maturational Neonatal Immune Deficiencies and Susceptibility to Group B Streptococcus Infection

The lack of natural processes of delivery and neonatal intensive care treatment lead to impaired cytokine responses later in life

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