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 and Ben Lu ()
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Yanyan Lu: Central South University
Ran Meng: Central South University
Xiangyu Wang: Central South University
Yajing Xu: Central South University
Yiting Tang: Central South University
Jianfeng Wu: Xiamen University
Qianqian Xue: Central South University
Songlin Yu: Central South University
Mingwu Duan: Central South University
Dongyong Shan: Central South University
Qingde Wang: University of Pittsburgh Medical Center
Haichao Wang: Northwell Health
Timothy R. Billiar: University of Pittsburgh Medical Center
Xianzhong Xiao: Central South University
Fangping Chen: Central South University
Ben Lu: Central South University

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11895-2

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