NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions

Abstract

Background Blood transfusion, a common basic supporting therapy, can lead to acute hemolytic transfusion reaction (AHTR). AHTR poses a great risk to patients through kidney function damage in a short time. Previous reports found that heme from destroyed red blood cells impaired kidney function, and NLR family pyrin domain containing 3 (NLRP3) inflammasome was augmented in case of kidney injury. However, the detailed mechanism regarding whether NLRP3 inflammasome is involved in kidney function injury in AHTR is not fully understood yet. Methods Hemolysis models were established by vein injection with human blood plasma or mouse heme from destroyed red blood cells. The injured renal tubular epithelial cells (RTECs) were evaluated by tubular damage markers staining in hemolysis models and in primary RTECs in vitro. The activation of NLRP3 inflammasome in RTECs by hemes was investigated by Western blot, ELISA, scanning electron microscopy, immunofluorescent staining, flow cytometry, and hemolysis models. NLRP3 gene knockout mice were employed to confirm these observations in vitro and in vivo. The binding between a novel inhibitor (66PR) and NLRP3 was affirmed by molecule docking and co‐immunoprecipitation. The rescue of 66PR on kidney function impairment was explored in murine hemolysis models. Results We found that heme could activate NLRP3 inflammasome in RTECs to induce kidney function injury. NLRP3 gene knockout could prevent the damage of RTECs caused by hemes and recover kidney function in AHTR. Moreover, NLRP3 inflammasome chemical inhibitor, 66PR, could bind to NLRP3 protein and inhibit inflammasome activation in RTECs, which consequently relieved the injury of RTECs caused by hemes, and alleviated kidney function damage in the AHTR model. Conclusions Hemes could activate NLRP3 inflammasome in RTECs, and a novel NLRP3 inflammasome inhibitor named 66PR relieved kidney function damage in AHTR. Our findings provided a new possible strategy to treat kidney function failure in AHTR.

RETRACTED: Macrophage SAMSN1 protects against sepsis-induced acute lung injury in mice

“…In addition, WBCs and the pro-inflammatory cytokines also contribute to reactive oxygen species (ROS) overproduction and oxidative damage [ 5 , 6 ]. Both pro-inflammatory cytokines and ROS are potential activators of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, which is consistent of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1, and promotes the maturation and release of pro-inflammatory cytokines (e.g., IL-1β and IL-18) [ [7] , [8] , [9] , [10] ]. Macrophages are the dominant inflammatory cells in the lungs, and play critical roles in sepsis-induced inflammation, oxidative stress and ALI [ 11 ].…”

Erythrocyte membrane biomimetic EGCG nanoparticles attenuate renal injury induced by diquat through the NF-κB/NLRP3 inflammasome pathway

“…Notably, the NLRP3 inflammasome has been linked to a multitude of both acute and chronic renal disorders ( Mulay, 2019 ; Liu et al, 2021 ). Animal studies have shown that inhibiting either TXNIP or NLRP3 can prevent acute kidney injury caused by rhabdomyolysis-induced ischemia-reperfusion injury ( Yuan et al, 2017 ).…”

The Interplay between Immune and Metabolic Pathways in Kidney Disease

“…Additionally, the NLRP3 inflammasome has been associated with the activation of other cell death mechanisms, including apoptosis and necroptosis, further highlighting its involvement in renal disease pathogenesis [ 93 ]. Inhibitors of the NLRP3 inflammasome, such as MCC950 and CY-09, have been shown to ameliorate renal injury and improve kidney function in various animal models of kidney disease [ 206 , 207 , 208 ]. However, the clinical efficacy of these inhibitors remains to be tested in human trials.…”