During apoptosis HMGB1 is translocated into apoptotic cell-derived membraneous vesicles

Schiller, Martin; Heyder, Petra; Ziegler, Saskia; Nießen, Anna; Claßen, Laura; Lauffer, Anna M.; Lorenz, Hanns‐Martin

doi:10.3109/08916934.2012.750302

Cited by 39 publications

(37 citation statements)

References 30 publications

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“…Data from our prior publications (11, 26, 44) as well as those from other investigators (45, 46)strongly indicates that the release of HMGB1 from the intestinal epithelium after TLR4 activation requires enterocyte apoptosis, that enterocyte apoptosis is induced by the activation of TLR4, and that the mechanisms leading to enterocyte apoptosis require the induction of endoplasmic reticulum stress on the enterocytes. Specifically, we have shown that TLR4 activation on the intestinal epithelium leads to the induction of ER stress within the intestinal epithelium which leads to enterocyte apoptosis (11).…”

Section: Discussionmentioning

confidence: 53%

Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis

Jia

Sodhi

Yamaguchi

et al. 2016

The Journal of Immunology

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We seek to define the mechanisms leading to the development of lung disease in the setting of neonatal necrotizing enterocolitis (NEC), a life-threatening gastrointestinal disease of premature infants characterized by the sudden onset of intestinal necrosis. NEC development in mice requires activation of the lipopolysaccharide receptor toll-like receptor-4 (TLR4) on the intestinal epithelium, through its effects on modulating epithelial injury and repair. Although NEC-associated lung injury is more severe than the lung injury that occurs in premature infants without NEC, the mechanisms leading to its development remain unknown. We now show that the TLR4 expression in the lung gradually increases during postnatal development, and that mice and humans with NEC-associated lung inflammation express higher levels of pulmonary TLR4 than age-matched controls. NEC in wild-type newborn mice resulted in significant pulmonary injury that was prevented by deletion of TLR4 from the pulmonary epithelium, indicating a role for pulmonary TLR4 in lung injury development. Mechanistically, intestinal epithelial TLR4 activation induced high mobility group box-1 (HMGB1) release from the intestine which activated pulmonary epithelial TLR4, leading to the induction of the neutrophil recruiting C-X-C motif chemokine-5 (CXCL5) and the influx of pro-inflammatory neutrophils to the lung. Strikingly, the aerosolized administration of a novel carbohydrate TLR4 inhibitor prevented CXCL5 upregulation and blocked NEC-induced lung injury in mice. These findings illustrate the critical role of pulmonary TLR4 in the development of NEC-associated lung injury, and suggest that inhibition of this innate immune receptor in the neonatal lung may prevent this devastating complication of NEC.

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Section: Discussionmentioning

confidence: 53%

Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis

Jia

Sodhi

Yamaguchi

et al. 2016

The Journal of Immunology

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“…In addition, molecules known to be involved in immune reactions, such as high mobility group box protein 1 (HMGB1), have been detected within apoptotic microparticles (Pisetsky, 2014;Schiller et al, 2013;Spencer et al, 2014). Defects in clearance of apoptotic material are considered a major pathogenetic factor in the development of SLE, and high levels of circulating apoptotic material have been found in many patients.…”

Section: Introductionmentioning

confidence: 99%

Apoptotic cell-derived membrane microparticles and IFN-α induce an inflammatory immune response

Nießen

Heyder

Krienke

et al. 2015

Journal of Cell Science

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A dysregulation in the clearance of apoptotic material is considered a major pathogenetic factor for the emergence of autoimmune diseases. Apoptotic-cell-derived membrane microparticles (AdMPs), which are released from the cell surface during apoptosis, have been implicated in the pathogenesis of autoimmunity. Also of importance are cytokines, such as interferon-α (IFN-α), which is known to be a major player in patients with systemic lupus erythematosus (SLE). This study investigates the combined effect of AdMPs and IFN-α on professional phagocytes. In the presence of IFN-α, phagocytosis of AdMPs by human monocytes was significantly increased in a dosedependent manner. The combination of AdMPs and raised IFN-α concentrations resulted in an increase in the secretion of proinflammatory cytokines and an upregulation of surface molecule expression involved in antigen uptake. In addition, macrophage polarisation was shifted towards a more inflammatory type of cell. The synergism between IFN-α and AdMPs seemed to be mediated by an upregulation of phosphorylated STAT1. Our results indicate that IFN-α, together with AdMPs, amplify the initiation and maintenance of inflammation. This mechanism might especially play a crucial role in disorders with a defective clearance of apoptotic material.

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“…8C). Recently, it was shown by Shiller et al [67] that High mobility group box protein B1 (HMGB1), a nuclear protein reportedly involved in structural organization of DNA and usually released from the necrotic cells or upon cellular activation, is translocated into the ACMV at apoptosis , also in paper in press, further supporting a proposed hypothesis.…”

Section: Fig 8 a -Apoptotic (Uv-b Irradiated) Hela Cells Produce Bimentioning

confidence: 56%

Sweet taste of cell death: role of carbohydrate recognition systems

Bilyy¹,

Stoika²

2013

Ukr.Biochem.J.

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During apoptosis HMGB1 is translocated into apoptotic cell-derived membraneous vesicles

Cited by 39 publications

References 30 publications

Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis

Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis

Apoptotic cell-derived membrane microparticles and IFN-α induce an inflammatory immune response

Sweet taste of cell death: role of carbohydrate recognition systems

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