Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease

Rotolo, Jimmy A.; Stancevic, Branka; Lu, Sydney X.; Zhang, Jianjun; Suh, David; King, C. H.; Kappel, Lucy W.; Murphy, Gëorge F.; Liu, Chen; Fuks, Zvi; Brink, Marcel R. van den; Kolesnick, Richard

doi:10.1182/blood-2008-11-191148

Cited by 24 publications

(17 citation statements)

References 49 publications

(76 reference statements)

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“…Thus presence of BMDCs at the site of CR might be explained by direct influx of BMDCs from intracranial vessels that have lost their BBB integrity. Previous data has reported that lymphocytes are recruited to the site of RT injury and can attach to vessel EC and infiltrate into normal brain parenchyma [27], [28]. We examined this possibility by staining for possible peripheral blood cells such as erythrocytes, granulocytes, megakaryocytes, Natural Killer cells, T and B cells using immunohistochemistry and immunofluorescence analysis in addition to 2PLM imaging.…”

Section: Discussionmentioning

confidence: 99%

High-Resolution In-Vivo Analysis of Normal Brain Response to Cranial Irradiation

2012

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Radiation therapy (RT) is a widely accepted treatment strategy for many central nervous system (CNS) pathologies. However, despite recognized therapeutic success, significant negative consequences are associated with cranial irradiation (CR), which manifests months to years post-RT. The pathophysiology and molecular alterations that culminate in the long-term detrimental effects of CR are poorly understood, though it is thought that endothelial injury plays a pivotal role in triggering cranial injury. We therefore explored the contribution of bone marrow derived cells (BMDCs) in their capacity to repair and contribute to neo-vascularization following CR. Using high-resolution in vivo optical imaging we have studied, at single-cell resolution, the spatio-temporal response of BMDCs in normal brain following CR. We demonstrate that BMDCs are recruited specifically to the site of CR, in a radiation dose and temporal-spatial manner. We establish that BMDCs do not form endothelial cells but rather they differentiate predominantly into inflammatory cells and microglia. Most notably we provide evidence that more than 50% of the microglia in the irradiated region of the brain are not resident microglia but recruited from the bone marrow following CR. These results have invaluable therapeutic implications as BMDCs may be a primary therapeutic target to block acute and long-term inflammatory response following CR. Identifying the critical steps involved in the sustained recruitment and differentiation of BMDCs into microglia at the site of CR can provide new insights into the mechanisms of injury following CR offering potential therapeutic strategies to counteract the long-term adverse effects of CR.

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Section: Discussionmentioning

confidence: 99%

High-Resolution In-Vivo Analysis of Normal Brain Response to Cranial Irradiation

2012

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“…Recent findings indicate that ceramides play important roles in inflammatory processes, and it has been shown that host acid SMase are imperative for maximal GVHD-associated pathology (10). In the aforementioned study, lack of host acid SMase reduced the acute inflammatory phase of GVHD, attenuating the cytokine storm (10). In the inflammatory disease cystic fibrosis, ceramides induce the upregulation of proinflammatory mediators, albeit via an unknown mechanism (11).…”

Section: Introductionmentioning

confidence: 94%

Ceramide synthesis regulates T cell activity and GVHD development

Sofi¹,

Heinrichs²,

Dany³

et al. 2017

JCI Insight

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“…Using clinically‐relevant mouse models of acute GVHD in which allogeneic bone marrow and T cells were transplanted into wild‐type and asmase −/− hosts, the authors identified host ASMase as critical for full blown GVHD. More specifically, the mechanism by which ASMase mediates CTL‐induced apoptosis of target cells (hepatocytes, small and large intestinal epithelium and endothelium, skin) appeared to require CRP formation on target cell membranes [132]. The lack of host ASMase, and in turn abrogation of CRP formation (defined using an ex vivo 2 cell model of GVHD in which in vivo‐activated T cell effector cells were coincubated with asmase +/+ or asmase −/− hepatocyte target cells), attenuated organ injury and consequent cytokine storm, decreasing morbidity and mortality.…”

Section: Manipulation Of Crps In Disease Treatmentmentioning

confidence: 99%

Ceramide‐rich platforms in transmembrane signaling

2010

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Recent evidence suggests that ceramide regulates stress signaling via reorganization of the plasma membrane. The focus of this review will be to discuss the mechanism by which acid sphingomyelinase (ASMase)-generated ceramide initiates transmembrane signaling in the plasma membrane exoplasmic leaflet. In particular, we review the unique biophysical properties of ceramide that render it proficient in formation of signaling domains termed ceramide-rich platforms (CRPs), and the role of CRPs in the pathophysiology of various diseases. The biomedical significance of CRPs makes these structures an attractive therapeutic target.

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Cytolytic T cells induce ceramide-rich platforms in target cell membranes to initiate graft-versus-host disease

Cited by 24 publications

References 49 publications

High-Resolution In-Vivo Analysis of Normal Brain Response to Cranial Irradiation

High-Resolution In-Vivo Analysis of Normal Brain Response to Cranial Irradiation

Ceramide synthesis regulates T cell activity and GVHD development

Ceramide‐rich platforms in transmembrane signaling

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