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

Dreschers, Stephan; Gille, Christian; Haas, Martin; Seubert, Florence; Platen, Christopher; Orlikowsky, Thorsten

doi:10.1371/journal.pone.0182415

Cited by 17 publications

(17 citation statements)

References 34 publications

(46 reference statements)

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“…We show that cell surface EGFR is increased in response to E. coli infection ( Figure 2(a) ), matching the results of another study that demonstrated upregulation of EGFR upon Helicobacter pylori infection [ 46 ]. It was already shown that TNF- α induces upregulation of EGFR [ 47 ], and in a previous study, we demonstrated that E. coli infection leads to TNF- α release, while PBMO displayed a distinctly increased TNF- α release compared to CBMO [ 48 ]. Therefore, we hypothesize that the increase in EGFR might be caused by E. coli infection and subsequent TNF- α release, thereby amplifying AREG function.…”

Section: Discussionmentioning

confidence: 82%

Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and Matrix Metalloproteinases

Platen

Dreschers

Reiss

et al. 2018

Mediators of Inflammation

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Neonates are highly susceptible to microbial infections which is partially attributable to fundamental phenotypic and functional differences between effector cells of the adult and neonatal immune system. The resolution of the inflammation is essential to return to tissue homeostasis, but given that various neonatal diseases, such as periventricular leukomalacia, necrotizing enterocolitis, or bronchopulmonary dysplasia, are characterized by sustained inflammation, newborns seem predisposed to a dysregulation of the inflammatory response. Targeted apoptosis of effector cells is generally known to control the length and extent of the inflammation, and previous studies have demonstrated that phagocytosis-induced cell death (PICD), a special type of apoptosis in phagocytic immune cells, is less frequently triggered in neonatal monocytes than in adult monocytes. We concluded that a rescue of monocyte PICD could be a potential therapeutic approach to target sustained inflammation in neonates. The EGFR ligand amphiregulin (AREG) is shed in response to bacterial infection and was shown to mediate cellular apoptosis resistance. We hypothesized that AREG might contribute to the reduced PICD of neonatal monocytes by affecting apoptosis signaling. In this study, we have examined a cascade of signaling events involved in extrinsic apoptosis by using a well-established in vitro E. coli infection model in monocytes from human peripheral blood (PBMO) and cord blood (CBMO). We found that CBMO shows remarkably higher pro-AREG surface expression as well as soluble AREG levels in response to infection as compared to PBMO. AREG increases intracellular MMP-2 and MMP-9 levels and induces cleavage of membrane-bound FasL through engagement with the EGF receptor. Our results demonstrate that loss of AREG rescues PICD in CBMO to the level comparable to adult monocytes. These findings identify AREG as a potential target for the prevention of prolonged inflammation in neonates.

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Section: Discussionmentioning

confidence: 82%

Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and Matrix Metalloproteinases

Platen

Dreschers

Reiss

et al. 2018

Mediators of Inflammation

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“…In the context of apoptosis, TNF-TNFR1 axis signals through caspase 3 and 8, and is mainly responsible for the host defense of pathogen ( 43 ) and anti-tumoral activities ( 44 ). The impaired regulation of this TNF receptor can cause autoimmune diseases, cancer, chronic infections and allergy ( 45 ).…”

Section: Pathogenic Role Of Tnf In Allergic Manifestationmentioning

confidence: 99%

The Key Role of TNF-TNFR2 Interactions in the Modulation of Allergic Inflammation: A Review

et al. 2018

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Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine, which is thought to play a major role in the pathogenesis of inflammatory diseases, including allergy. TNF is produced at the early stage of allergen sensitization, and then continues to promote the inflammation cascade in the effector phase of allergic reactions. Consequently, anti-TNF treatment has been proposed as a potential therapeutic option. However, recent studies reveal anti-intuitive effects of TNF in the activation and proliferative expansion of immunosuppressive Tregs, tolerogenic DCs and MDSCs. This immunosuppressive effect of TNF is mediated by TNFR2, which is preferentially expressed by immunosuppressive cells. These findings redefine the role of TNF in allergic reaction, and suggest that targeting TNF-TNFR2 interaction itself may represent a novel strategy in the treatment of allergy.

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“…One recent study showed that TNF-α can mediate cell death by ligating its receptor TNF receptor 1 (TNFR1) and uptake of ligand-bound TNFR1 activates caspase-8 and -3 in cord blood monocytes. 29 The reduced levels of bax in this study suggest a different apoptosis pathway induced by TNF-α after SAH. Collectively, these results strongly suggest the differential molecular mechanisms of action for anti-TNF-α antibody in different brain regions during the inhibition of apoptosis after SAH.…”

Section: Discussionmentioning

confidence: 60%

Anti-TNF-alpha antibody attenuates subarachnoid hemorrhage-induced apoptosis in the hypothalamus by inhibiting the activation of Erk

Ma¹,

Dong²,

Gao³

et al. 2018

NDT

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BackgroundSubarachnoid hemorrhage (SAH) can induce apoptosis in many regions of the brain including the cortex and hippocampus. However, few studies have focused on apoptosis in the hypothalamus after SAH. Although some antiapoptotic strategies have been developed for SAH, such as anti-tumor necrosis factor-alpha (TNF-α) antibody, the molecular mechanisms underlying this condition have yet to be elucidated. Therefore, the purpose of this study was to evaluate whether SAH could induce apoptosis in the hypothalamus and identify the potential molecular mechanisms underlying the actions of anti-TNF-α antibody, as a therapeutic regimen, upon apoptosis.Materials and methodsSAH was induced in a rat model. Thirty minutes prior to SAH, anti-TNF-α antibody or U0126, an extracellular signal-regulated kinase (Erk) inhibitor, was microinjected into the left lateral cerebral ventricle. In addition, phorbol-12-myristate-13-acetate was injected intraperitoneally immediately after the anti-TNF-α antibody microinjection. Then, real-time polymerase chain reaction, Western blotting and immunohistochemistry were used to detect the expression of caspase-3, bax, bcl-2, phosphorylated Erk (p-Erk) and Erk. Finally, anxiety-like behavior was identified by using open field.ResultsLevels of caspase-3, bax and bcl-2, all showed a temporary rise after SAH in the hypothalamus, indicating the induction of apoptosis in this brain region. Interestingly, we found that the microinjection of anti-TNF-α antibody could selectively block the elevated levels of bax, suggesting the potential role of anti-TNF-α antibody in the inhibition of SAH-induced apoptosis in the hypothalamus. Moreover, we found that Erk activation was necessary for apoptosis after SAH and that the microinfusion of anti-TNF-α antibody could inhibit apoptosis by suppressing the increase of p-Erk in the hypothalamus. Finally, our data indicated that the infusion of anti-TNF-α antibody could improve anxiety-like behavior.ConclusionCollectively, our data demonstrate that anti-TNF-α antibody attenuates apoptosis in the hypothalamus by inhibiting the activation of Erk, which plays an important role in the treatment of SAH.

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

Cited by 17 publications

References 34 publications

Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and Matrix Metalloproteinases

Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and Matrix Metalloproteinases

The Key Role of TNF-TNFR2 Interactions in the Modulation of Allergic Inflammation: A Review

Anti-TNF-alpha antibody attenuates subarachnoid hemorrhage-induced apoptosis in the hypothalamus by inhibiting the activation of Erk

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