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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2409-2417
Number of pages9
JournalBiology of Blood and Marrow Transplantation
Volume24
Issue number12
Early online date25 Jul 2018
DOIs
Publication statusE-pub ahead of print - 25 Jul 2018

Keywords

  • Allogeneic hematopoietic cell transplantation
  • Gene knockout
  • Graft-versus-host disease
  • Inflammasome
  • Liver injury
  • NLRP3

Fingerprint Dive into the research topics of 'Loss of NLRP3 Function Alleviates Murine Hepatic Graft-versus-Host Disease'. Together they form a unique fingerprint.

Cite this