The Role of TNFα- and IFNγ-induced PANoptosis in Renal Vascular Endothelial Cells: Implications for OMDT

Abstract

Abstract This study mainly investigated the mechanism underlying the joint effects of TNFα and IFNγ on renal injury and preliminarily elucidated the influence of the combination of these two agents on the efficacy of recombinant human tumor necrosis factor-α receptor II fusion protein (rh TNFR:Fc) in the treatment of occupational medicamentose-like dermatitis due to trichloroethylene (TCE) (OMDT) patients. The level of peripheral TNFα and IFNγ of OMDT patients were measured to analyze their joint effects on renal function and vascular endothelial cells (ECs) injury. In vivo and in vitro studies were used to investigate the mechanism of TNFα- and IFNγ-induced ECs PANoptosis. Results showed that the combination of TNFα and IFNγ was significantly associated with kidney function and renal ECs injury. TCE-sensitized positive mice had elevated PANoptosis-related markers in renal ECs, and the injection of a TNFα and IFNγ neutralizing antibody significantly inhibited PANoptosis. In vitro studies revealed that TNFα- and IFNγ-induced ECs PANoptosis could be reversed by silencing interferon regulatory factor 1 (IRF1). In conclusion, peripheral TNFα and IFNγ levels were associated with kidney function. PANoptosis can be induced by the combination of TNFα and IFNγ, IRF1 was the master protein that regulates the assembly of the PANoptosome.