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

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.

Role of T cell immune response cDNA 7 on the pathology of acute graft‑versus‑host disease

“…The health and behavior of the mice were monitored daily. Recipient mice were sacrificed by cervical dislocation at different time points [days 7, 14, 21, 28 and 35 post-transplantation according to the previous study (23)] during a total research period of 40 days post-transplantation, according to our previous study (22). A total of 3 mice per experimental group were sacrificed at each time point.…”

Current Advances in Graft-Versus-Host Disease After Intestinal Transplantation

“…61 Animal studies of hepatic GvHD due to HSCT have also underscored the role of the NLRP3 inflammasome. 62 However, in ITx, it remains to be determined whether early inactivation of the inflammasome could promote enhanced engraftment, attenuate innate immune responses, and overall reduce risk of both allograft rejection and GvHD (Figure 1). Early inactivation of NLRP3 via inhibition of miR-155 or enhancement of suppressor function by myeloid-derived suppressor cells could potentially prevent GvHD in ITx.…”

Inflammasomes—New Contributors to Blood Diseases

“…Thus, its impairment may ameliorate GvHD in vivo, which could be mediated by microRNA-155 [ 62 ]. As the NLRP3 inflammasome is associated with multiple risks in GvHD [ 63 ], studies have examined its role in hepatic complications in a GvHD murine model. After the conditioning, upregulated expression of both IL-1β and IL-18 was found in hepatic tissues concomitantly with elevated NLRP3 and caspase-1 mRNA [ 64 ].…”

“…Consequently, administration of the NLRP3 inflammasome inhibitor, BAY 11-7082, alleviated GvHD symptoms and downregulated the expression of NLRP3 and caspase-1 [ 64 ]. Accordingly, NLRP3-knockout mice displayed decreased liver infiltration and less severe injuries [ 63 ].…”