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.
Highlights
Acute graft-versus-host disease (GVHD) remains a major obstacle for the wider usage of allogeneic hematopoietic stem cell transplantation, which is an effective therapy for hematopoietic malignancy
The success of allogeneic hematopoietic stem cell transplantation, a standard therapy for conditions such as hematopoietic malignancies and inherited hematopoietic disorders, is limited by the mortality and morbility associated with graft-versus-host disease (GVHD)[1,2]
To determine the role of caspase-11 in GVHD following allo-HSCT, T cells purified from WT mice were transplanted together with bone marrow transplantation (BM) into lethally irradiated major histocompatibility complex (MHC)-mismatched WT or Caspase-11deficient recipient mice
Summary
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. Allo-HSCT recipient mice that express a signaling-deficient Tlr[4] mutant developed fulminant GVHD and increased intestinal damage compared to their wild-type (WT) counterparts[8] These observations raise a possibility that LPS or Gram-negative bacteria might enhance GVHD through TLR4-independent signaling pathways. Upon activation by intracellular LPS, caspase-11 oligomerizes into protein complexes and enzymatically cleaves gasdermin D (GSDMD) into pore-forming peptides, leading to a lytic form of cell death, termed pyroptosis[16,17,18]. This process destroys the intracellular niche for microbes and triggers inflammation by releasing alarmins, such as interleukin-1α (IL-1α)[12,13,15]. Loss of caspase-11 renders mice susceptible to Burkholderia pseudomallei, a Gram-negative bacterium endemic to Southeast Asia that causes melioidosis[12]
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