TNF-α synergises with IFN-γ to induce caspase-8-JAK1/2-STAT1-dependent death of intestinal epithelial cells
| Autor: | Subhasree Rajaram, Simon S. McDade, Daniel B. Longley, Panagiota Stamou, Pedro Aza-Blanc, Ciaran M. Lee, Jerzy A. Woznicki, Karine Regazzoni, Nisha Saini, Nyree Crawford, Kenneth Nally, Fergus Shanahan, Jane McCarthy, Agnieszka Skowyra, Syed Akbar Zulquernain, Milan Bustamante-Garrido, Bradford L McRae, Silvia Melgar, Peter Flood |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Programmed cell death Colon Necroptosis Biopsy Immunology Apoptosis Biology Caspase 8 Article Cellular and Molecular Neuroscience RIPK1 Interferon-gamma SDG 3 - Good Health and Well-being Cell Line Tumor Cell death and immune response Humans Kinome Cell Death QH573-671 Kinase Tumor Necrosis Factor-alpha Tumour-necrosis factors Epithelial Cells Cell Biology Janus Kinase 1 Janus Kinase 2 Mitochondria Intestines Organoids Crohn's disease STAT1 Transcription Factor Cytoprotection Receptors Tumor Necrosis Factor Type I Cancer research Tumor necrosis factor alpha RNA Interference Interferons Cytology Signal Transduction |
| Zdroj: | Woznicki, J A, Saini, N, Flood, P, Rajaram, S, Lee, C M, Stamou, P, Skowyra, A, Bustamante-Garrido, M, Regazzoni, K, Crawford, N, McDade, S S, Longley, D B, Aza-Blanc, P, Shanahan, F, Zulquernain, S A, McCarthy, J, Melgar, S, McRae, B L & Nally, K 2021, ' TNF-α synergises with IFN-γ to induce caspase-8-JAK1/2-STAT1-dependent death of intestinal epithelial cells ', Cell, Death & Disease, vol. 12, 864 . https://doi.org/10.1038/s41419-021-04151-3 Cell Death & Disease Cell Death and Disease, Vol 12, Iss 10, Pp 1-15 (2021) |
| DOI: | 10.1038/s41419-021-04151-3 |
| Popis: | Rewiring of host cytokine networks is a key feature of inflammatory bowel diseases (IBD) such as Crohn’s disease (CD). Th1-type cytokines—IFN-γ and TNF-α—occupy critical nodes within these networks and both are associated with disruption of gut epithelial barrier function. This may be due to their ability to synergistically trigger the death of intestinal epithelial cells (IECs) via largely unknown mechanisms. In this study, through unbiased kinome RNAi and drug repurposing screens we identified JAK1/2 kinases as the principal and nonredundant drivers of the synergistic killing of human IECs by IFN-γ/TNF-α. Sensitivity to IFN-γ/TNF-α-mediated synergistic IEC death was retained in primary patient-derived intestinal organoids. Dependence on JAK1/2 was confirmed using genetic loss-of-function studies and JAK inhibitors (JAKinibs). Despite the presence of biochemical features consistent with canonical TNFR1-mediated apoptosis and necroptosis, IFN-γ/TNF-α-induced IEC death was independent of RIPK1/3, ZBP1, MLKL or caspase activity. Instead, it involved sustained activation of JAK1/2-STAT1 signalling, which required a nonenzymatic scaffold function of caspase-8 (CASP8). Further modelling in gut mucosal biopsies revealed an intercorrelated induction of the lethal CASP8-JAK1/2-STAT1 module during ex vivo stimulation of T cells. Functional studies in CD-derived organoids using inhibitors of apoptosis, necroptosis and JAKinibs confirmed the causative role of JAK1/2-STAT1 in cytokine-induced death of primary IECs. Collectively, we demonstrate that TNF-α synergises with IFN-γ to kill IECs via the CASP8-JAK1/2-STAT1 module independently of canonical TNFR1 and cell death signalling. This non-canonical cell death pathway may underpin immunopathology driven by IFN-γ/TNF-α in diverse autoinflammatory diseases such as IBD, and its inhibition may contribute to the therapeutic efficacy of anti-TNFs and JAKinibs. |
| Databáze: | OpenAIRE |
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