Caspase-11 signaling enhances graft-versus-host disease

Yanyan Lu, Ran Meng, Xiangyu Wang, Yajing Xu, Yiting Tang, Jianfeng Wu, Qianqian Xue, Songlin Yu, Mingwu Duan, Dongyong Shan, Qingde Wang, Haichao Wang, Timothy R. Billiar, Xianzhong Xiao, Fangping Chen, Ben Lu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Article number4044
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - 1 Dec 2019
Externally publishedYes

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