Caspase-11 signaling enhances graft-versus-host disease.
Nat Commun
; 10(1): 4044, 2019 09 06.
Article
em En
| MEDLINE
| ID: mdl-31492850
ABSTRACT
Acute graft-versus-host disease (GVHD) remains a major obstacle for the wider usage of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an effective therapy for hematopoietic malignancy. Here we show that caspase-11, the cytosolic receptor for bacterial endotoxin (lipopolysaccharide LPS), enhances GVHD severity. Allo-HSCT markedly increases the LPS-caspase-11 interaction, leading to the cleavage of gasdermin D (GSDMD). Caspase-11 and GSDMD mediate the release of interleukin-1α (IL-1α) in allo-HSCT. Deletion of Caspase-11 or Gsdmd, inhibition of LPS-caspase-11 interaction, or neutralizing IL-1α uniformly reduces intestinal inflammation, tissue damage, donor T cell expansion and mortality in allo-HSCT. Importantly, Caspase-11 deficiency does not decrease the graft-versus-leukemia (GVL) activity, which is essential to prevent cancer relapse. These findings have major implications for allo-HSCT, as pharmacological interference with the caspase-11 signaling might reduce GVHD while preserving GVL activity.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Transplante de Células-Tronco Hematopoéticas
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Neoplasias Hematológicas
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Caspases
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Doença Enxerto-Hospedeiro
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article