Loss of NLRP3 Function Alleviates Murine Hepatic Graft-versus-Host Disease

Shengyun Zhu; Peipei Shi; Chaoran Lv; Huiqi Li; Bin Pan; Wei Chen; Kai Zhao; Zhiling Yan; Chong Chen; Gary J Loake; Mingshan Niu; Lingyu Zeng; Kailin Xu

doi:10.1016/j.bbmt.2018.07.026

Loss of NLRP3 Function Alleviates Murine Hepatic Graft-versus-Host Disease

Biol Blood Marrow Transplant. 2018 Dec;24(12):2409-2417. doi: 10.1016/j.bbmt.2018.07.026. Epub 2018 Jul 25.

Authors

Shengyun Zhu¹, Peipei Shi², Chaoran Lv², Huiqi Li², Bin Pan¹, Wei Chen¹, Kai Zhao¹, Zhiling Yan¹, Chong Chen¹, Gary J Loake³, Mingshan Niu¹, Lingyu Zeng¹, Kailin Xu⁴

Affiliations

¹ Institute of Blood Diseases, Xuzhou Medical University, Xuzhou, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
² Institute of Blood Diseases, Xuzhou Medical University, Xuzhou, China.
³ Institute of Molecular Plant Sciences, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom.
⁴ Institute of Blood Diseases, Xuzhou Medical University, Xuzhou, China; Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. Electronic address: lihmd@163.com.

PMID: 30053645
DOI: 10.1016/j.bbmt.2018.07.026

Abstract

NLRP3 is associated with multiple risks in graft-versus-host disease, though unifying principles for these findings remain largely unknown. To explore the effects and mechanisms of the absence of NLRP3 function on hepatic graft-versus-host-disease, we established an allogeneic hematopoietic cell transplantation mice model by infusing bone marrow mononuclear cells and spleno-T cells of the BALB/c mouse into either NLRP3 knockout (NLRP3^-/- ) or wild-type C57BL/6 mice. Elevated inflammatory cell infiltration, liver fibrosis, and secretions of alanine aminotransferase (ALT) and aspartate transaminase (AST), together with weight loss, were observed in C57BL/6 recipients after transplantation. However, moderate injury pathology was detected in the liver of NLRP3^-/- recipients at day 14, which gradually improved over time. Likewise, proinflammatory cytokine IL-1β, a downstream effecter of NLRP3 inflammasome activation, showed significantly lower expression (P < .05) in the liver of NLRP3^-/- recipients relative to C57BL/6 recipients at day 7 and day 21. Moreover, compared with C57BL/6 recipients, the expression of both TNF-α and IL-1β were decreased 3-fold and 4.7-fold, respectively, at day 21 in NLRP3^-/- recipients. Interestingly, NLRP1a was expressed at a significantly reduced level in the liver of NLRP3^-/- recipients (P < .001). Furthermore, systemic inflammation was analyzed by measuring the concentration of IL-1β and adenosine triphosphate (ATP) in serum. The concentration of IL-1β achieved a maximum at day 14, then decreased at day 21 and day 28 in NLRP3^-/- recipients. In contrast, the concentration of IL-1β in C57BL/6 recipients gradually increased from day 7 to day 28. ATP levels reduced from day 7 to day 28 in NLRP3^-/- recipients, but were extremely high in C57BL/6 recipients from day 14 to day 28 (P < .01). The decreased levels of P2X7R were connected to less ATP in NLRP3^-/- recipients at day 21 and day 28. In conclusion, NLRP3 knockout in recipients could significantly relieve liver injury after transplantation and block the NLRP3 inflammasome pathway, thus providing a promising strategy for the treatment of graft-versus-host disease prophylaxis.

Keywords: Allogeneic hematopoietic cell transplantation; Gene knockout; Graft-versus-host disease; Inflammasome; Liver injury; NLRP3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Graft vs Host Disease / genetics*
Hematopoietic Stem Cell Transplantation / methods*
Liver / pathology*
Mice
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
Transplantation, Homologous / methods*

Substances

NLR Family, Pyrin Domain-Containing 3 Protein