Diabetic pregnancy activates the innate immune response through TLR5 or TLR1/2 on neonatal monocyte

Yanai, Sakika; Tokuhara, Daisuke; Tachibana, Daisuke; Sakashita, Yuko; Shintaku, Haruo; Koyama, Masayasu

doi:10.1016/j.jri.2016.06.007

Cited by 18 publications

(15 citation statements)

References 41 publications

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“…S6B). This agrees with previous reports that high concentrations of Pam3CSK4 can lead to saturated secretion of cytokines in macrophages and monocytes (56,(61)(62)(63).…”

Section: Synergistic Induction Of Tumor Necrosis Factor α Secretion Rsupporting

confidence: 93%

Geometrical reorganization of Dectin-1 and TLR2 on single phagosomes alters their synergistic immune signaling

Yan

2019

Proc. Natl. Acad. Sci. U.S.A.

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Receptors of innate immune cells function synergistically to detect pathogens and elicit appropriate immune responses. Many receptor pairs also appear “colocalized” on the membranes of phagosomes, the intracellular compartments for pathogen ingestion. However, the nature of the seemingly receptor colocalization and the role it plays in immune regulation are unclear, due to the inaccessibility of intracellular phagocytic receptors. Here, we report a geometric manipulation technique to directly probe the role of phagocytic receptor “colocalization” in innate immune regulation. Using particles with spatially patterned ligands as phagocytic targets, we can decouple the receptor pair, Dectin-1 and Toll-like receptor (TLR)2, to opposite sides on a single phagosome or bring them into nanoscale proximity without changing the overall membrane composition. We show that Dectin-1 enhances immune responses triggered predominantly by TLR2 when their centroid-to-centroid proximity is <500 nm, but this signaling synergy diminishes upon receptor segregation beyond this threshold distance. Our results demonstrate that nanoscale proximity, not necessarily colocalization, between Dectin-1 and TLR2 is required for their synergistic regulation of macrophage immune responses. This study elucidates the relationship between the spatial organization of phagocytic receptors and innate immune responses. It showcases a technique that allows spatial manipulation of receptors and their signal cross-talk on phagosomes inside living cells.

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“…S6B). This agrees with previous reports that high concentrations of Pam3CSK4 can lead to saturated secretion of cytokines in macrophages and monocytes (56,(61)(62)(63).…”

Section: Synergistic Induction Of Tumor Necrosis Factor α Secretion Rsupporting

confidence: 93%

Geometrical reorganization of Dectin-1 and TLR2 on single phagosomes alters their synergistic immune signaling

Yan

2019

Proc. Natl. Acad. Sci. U.S.A.

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“…TLR signaling is important for triggering and modulating adaptive immune response through activation of DCs [ 42 , 43 ]. Flagellin, a specific ligand for TLR5, plays an important role in activating immune response via triggering TLR signaling [ 44 , 45 ]. A bacterial filament protein, flagellin incombination with siRNA-SOCS1 modified-DC vaccine was found to be more potent and persistent than a commercial TLR agonist in both murine and human DCs and displays a superior ability to activate HCV antigen-specific cellular and humoral immune responses [ 46 , 47 ].…”

Section: Introductionmentioning

confidence: 99%

Phase I clinical trial of a novel autologous modified-DC vaccine in patients with resected NSCLC

Song

et al. 2017

BMC Cancer

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BackgroundThe primary aim of this study was to evaluate the safety of a novel dendritic cell (DC) vaccine pulsed with survivin and MUC1, silenced with suppressor of cytokine signaling 1 (SOCS1), and immune stimulated with flagellin for patients with stage I to IIIA non-small cell lung cancer (NSCLC) in a phase I open-label, uncontrolled, and dose-escalation trial. Moreover, we evaluate the potential efficacy of this modified DC vaccine as secondary aim.MethodsThe patients were treated with the vaccine at 1 × 106, 1 × 107and the maximum dose 8 × 107 at day 7, 14, and 21 after characterization of the vaccine phenotype by flow cytometry. The safety of the vaccine was assessed by adverse events, and the efficacy by the levels of several specific tumor markers and the patient quality of life.ResultsThe vaccine was well tolerated without dose-limiting toxicity even at higher doses. The most common adverse event reported was just grade 1 flu-like symptoms without unanticipated or serious adverse event. A significant decrease in CD3 + CD4 + CD25 + Foxp3+ T regulatory (Treg) cell number and increase in TNF-α and IL-6 were observed in two patients. Two patients showed 15% and 64% decrease in carcino-embryonic antigen and CYFRA21, respectively. The vaccination with the maximum dose significantly improved the patients’quality of life when administered at the highest dose. More importantly, in the long-term follow-up until February 17, 2017, 1 patient had no recurrence, 1 patients had a progressive disease (PD), and 1 patient was died in the low dose group. In the middle dose group, all 3 patients had no recurrence. In the high dose group, 1 patient was died, 1 patient had a PD, and the other 7 patients had no recurrence.ConclusionsWe provide preliminary data on the safety and efficacy profile of a novel vaccine against non-small cell lung cancer, which was reasonably well tolerated, induced modest antitumor activity without dose-limiting toxicity, and improved patients’ quality of life. Further more, the vaccine maybe a very efficacious treatment for patients with resected NSCLC to prevent recurrence. Our findings on the safety and efficacy of the vaccine in this phase I trial warrant future phase II/III clinical trial.

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“…GDM alters the expression of AGER, CCL2 , and CCL8 which are associated with generalized innate immune response (Money et al 2017). GDM also induces excessive inflammatory activation in neonatal monocytes via TLR-2 (Yanai et al 2016). Placenta is sensitive to the hyperglycemic milieu and responses with various adaptive changes of the structure and function.…”

Section: Discussionmentioning

confidence: 99%

Differences in the Expression of TLR-2, NOD2, and NF-κB in Placenta Between Twins

Szylberg

Bodnar

Lebioda

et al. 2018

Arch. Immunol. Ther. Exp.

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Dizygotic twins share the same type of genetic relationship as non-twin siblings. Whereas monozygotic (MZ) twins are considered to have identical genetic material, they still differ. There is a number of reasons for early MZ twin discordance, including differences in the in utero environment, stochasticity, genetic mosaicism, and epigenetic factors. During gestation, the efficient innate immune system is of utmost importance. Our study was based on immunohistochemical evaluation of the differences in innate immune protein expression (TLR-2, NOD2, and NF-κB) in the 95 placentas between twins. Our study revealed statistical significant differences between diamniotic–dichorionic and monoamniotic–dichorionic twins. Monoamniotic–monochorionic twins exhibited no significant differences in protein expressions. To identify epigenetic factors causing the differences between twins, we made a series of comparisons with clinical data. The study revealed more cases with infections, miscarriages, in vitro fertilization, and premature rupture of membranes within the group with higher differences level of NF-κB, NOD2 and TLR-2 between twins. In case of twin-to-twin transfusion syndrome, there were no significant differences in innate immune protein expressions between twins. These results show that dissimilar genetic material and separate in utero environment promote discordance in innate immune protein expressions between twins. Moreover, additional blood flow between twins may be favorable in life-threatening conditions ensuring similar microenvironment.

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Diabetic pregnancy activates the innate immune response through TLR5 or TLR1/2 on neonatal monocyte

Cited by 18 publications

References 41 publications

Geometrical reorganization of Dectin-1 and TLR2 on single phagosomes alters their synergistic immune signaling

Geometrical reorganization of Dectin-1 and TLR2 on single phagosomes alters their synergistic immune signaling

Phase I clinical trial of a novel autologous modified-DC vaccine in patients with resected NSCLC

Differences in the Expression of TLR-2, NOD2, and NF-κB in Placenta Between Twins

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