澳大利亚墨尔本大学James E. Vince、Rebecca Feltham等研究人员合作发现，干扰素-γ通过caspase-8和线粒体细胞死亡途径为巨噬细胞提供病原体配体诱导的杀伤力。该项研究成果于2022年2月8日在线发表在《免疫》上。

Title: Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway

Author: Daniel S. Simpson, Jiyi Pang, Ashley Weir, Isabella Y. Kong, Melanie Fritsch, Maryam Rashidi, James P. Cooney, Kathryn C. Davidson, Mary Speir, Tirta M. Djajawi, Sebastian Hughes, Liana Mackiewicz, Merle Dayton, Holly Anderton, Marcel Doerflinger, Yexuan Deng, Allan Shuai Huang, Stephanie A. Conos, Hazel Tye, Seong H. Chow, Arfatur Rahman, Raymond S. Norton, Thomas Naderer, Sandra E. Nicholson, Gaetan Burgio, Si Ming Man, Joanna R. Groom, Marco J. Herold, Edwin D. Hawkins, Kate E. Lawlor, Andreas Strasser, John Silke, Marc Pellegrini, Hamid Kashkar, Rebecca Feltham, James E. Vince

Issue&Volume: 2022-02-08

Abstract: Cell death plays an important role during pathogen infections. Here, we report thatinterferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced deaththat requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity,which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptoticcaspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase(iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophagekilling required iNOS, which licensed apoptotic caspase-8 activity and reduced theBAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induceddisease in mice, while caspase-8 caused lethality independent of iNOS in a model ofhemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licensesprogrammed cell death, which may explain how nitric oxide impacts disease severityin SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.

DOI: 10.1016/j.immuni.2022.01.003

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00032-2