Caspase-11 signaling enhances graft-versus-host disease

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.

Channelling inflammation: gasdermins in physiology and disease

“…In a mouse bone marrow transplantation model, a recent study indicated that radiation causes severe damage to bones and spleen through NLRP3- and AIM2-mediated GSDMD-dependent pyroptosis, which is prevented only when GSDMD is deficient in both donor and host cells 152 . Activation of the noncanonical inflammasome pathway in mice worsens graft-versus-host disease, and Gsdmd deficiency reduces intestinal inflammation, tissue damage, donor T cell expansion and mortality in allogeneic haematopoietic stem cell transplantation 153 . Genetic deficiency or knockdown studies have also implicated GSDMD in the pathogenesis of alcoholic hepatitis, nonalcoholic steatohepatitis, noninfectious liver injury and ischaemia–reperfusion injury in humans and mice 154 – 158 .…”

Inflammasome‐associated cell death: Pyroptosis, apoptosis, and physiological implications

“…Following HSCT, circulating LPS activates caspase-11, which induces the GSDMD-dependent release of IL-1α, thereby enhancing donor T-cell expansion and GVHD. 123 The blockade of caspase-11 signaling ameliorates HSCTinduced GVHD without affecting graft-versus-leukemia activity. Psoriasis is a chronic inflammatory skin disease that is characterized by scaling, erythema, and acanthosis with the infiltration of immune cells.…”

“…While allogeneic hematopoietic stem cell transplantation (HSCT) is an effective therapy for hematopoietic tumors, its beneficial effects are limited by graft‐versus‐host disease (GVHD). Following HSCT, circulating LPS activates caspase‐11, which induces the GSDMD‐dependent release of IL‐1α, thereby enhancing donor T‐cell expansion and GVHD 123 . The blockade of caspase‐11 signaling ameliorates HSCT‐induced GVHD without affecting graft‐versus‐leukemia activity.…”

Targeting Cytokines, Pathogen-Associated Molecular Patterns, and Damage-Associated Molecular Patterns in Sepsis via Blood Purification

“…Based on this new finding, LPS in the blood is taken up by vascular endothelial cells and causes lung injury by pyrotosis [37]. LPS-induced pyroptosis has also been confirmed in organs besides the lungs, such as in tubular epithelial cells [38], cardiomyocytes [39], graft-versus-host disease [40], and neutrophils [41]. The gut, which is considered an important source of LPS in the bloodstream, has a neutralization mechanism for LPS [42], and the disruption of the intestinal barrier The first signal is initiated by multiple TLRs in response to PAMPs (signal 1: priming) while the second signal in response to intracellular LPS triggers caspase-11 activation (signal 2: triggering), leading to lethal septic shock.…”