COVID-19 patients with high TNF/IFN-γ levels show hallmarks of PANoptosis, an inflammatory cell death

Palacios, Yadira; Ramón‐Luing, Lucero A.; Ruíz, Andy; García-Martínez, Alicia; Sánchez-Monciváis, Anahí; Barreto-Rodríguez, Omar; Falfán-Valencia, Ramcés; Pérez-Rubio, Gloría; Medina-Quero, Karen; Buendía-Roldán, Ivette; Chávez‐Galán, Leslie

doi:10.1016/j.micinf.2023.105179

Cited by 13 publications

(6 citation statements)

References 40 publications

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“…Actually, our findings are in contrast with the literature data that describe a synergism of IFNγ plus TNFα as a trigger for apoptosis and pyroptosis in BEAS-2B airway epithelial cells [ 35 ]. Similarly, the same combination of cytokines has been described as an effective approach to induce cell death in cancer cells [ 36 ], and high levels of TNFα and IFNγ are supposed to be responsible for the inflammatory cell death in severe COVID-19 patients [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Regarding SARS-CoV-2 infection, the exact role of IFNγ appears complex and contradictory findings are reported [ 25 ]. Indeed, although IFNγ is able to inhibit the SARS-CoV-2 replication [ 26 , 27 ], elevated levels of IFNγ, especially in combination with TNFα, aggravates the systemic inflammation causing tissue injury and organ failure [ 28 , 29 ]. On the other hand, it is also reported that the expression of IFNγ is significantly reduced in severe COVID-19 hospitalized patients [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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IRF1 Mediates Growth Arrest and the Induction of a Secretory Phenotype in Alveolar Epithelial Cells in Response to Inflammatory Cytokines IFNγ/TNFα

Recchia Luciani,

Barilli,

Visigalli

et al. 2024

IJMS

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In COVID-19, cytokine release syndrome can cause severe lung tissue damage leading to acute respiratory distress syndrome (ARDS). Here, we address the effects of IFNγ, TNFα, IL-1β and IL-6 on the growth arrest of alveolar A549 cells, focusing on the role of the IFN regulatory factor 1 (IRF1) transcription factor. The efficacy of JAK1/2 inhibitor baricitinib has also been tested. A549 WT and IRF1 KO cells were exposed to cytokines for up to 72 h. Cell proliferation and death were evaluated with the resazurin assay, analysis of cell cycle and cycle-regulator proteins, LDH release and Annexin-V positivity; the induction of senescence and senescence-associated secretory phenotype (SASP) was evaluated through β-galactosidase staining and the quantitation of secreted inflammatory mediators. While IL-1 and IL-6 proved ineffective, IFNγ plus TNFα caused a proliferative arrest in A549 WT cells with alterations in cell morphology, along with the acquisition of a secretory phenotype. These effects were STAT and IRF1-dependent since they were prevented by baricitinib and much less evident in IRF1 KO than in WT cells. In alveolar cells, STATs/IRF1 axis is required for cytokine-induced proliferative arrest and the induction of a secretory phenotype. Hence, baricitininb is a promising therapeutic strategy for the attenuation of senescence-associated inflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

IRF1 Mediates Growth Arrest and the Induction of a Secretory Phenotype in Alveolar Epithelial Cells in Response to Inflammatory Cytokines IFNγ/TNFα

Recchia Luciani,

Barilli,

Visigalli

et al. 2024

IJMS

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“…1 Patients with high TNF and IFNγ levels are predominant in severe COVID-19 status, displaying a hallmark of PANoptosis. 95 Specifically, co-treated TNFα and IFNγ activate the JAK/STAT1/IRF1 signaling, provoking nitric oxide (NO) formation, subsequently triggering caspase-8/FADD-based PANoptosis.…”

Section: Coronavirus Disease 2019 (Covid-19)mentioning

confidence: 99%

PANoptosis: Mechanisms, biology, and role in disease

Sun,

Yang,

Meng

et al. 2023

Immunological Reviews

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SummaryCell death can be executed through distinct subroutines. PANoptosis is a unique inflammatory cell death modality involving the interactions between pyroptosis, apoptosis, and necroptosis, which can be mediated by multifaceted PANoptosome complexes assembled via integrating components from other cell death modalities. There is growing interest in the process and function of PANoptosis. Accumulating evidence suggests that PANoptosis occurs under diverse stimuli, for example, viral or bacterial infection, cytokine storm, and cancer. Given the impact of PANoptosis across the disease spectrum, this review briefly describes the relationships between pyroptosis, apoptosis, and necroptosis, highlights the key molecules in PANoptosome formation and PANoptosis activation, and outlines the multifaceted roles of PANoptosis in diseases together with a potential for therapeutic targeting. We also discuss important concepts and pressing issues for future PANoptosis research. Improved understanding of PANoptosis and its mechanisms is crucial for identifying novel therapeutic targets and strategies.

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“…Zinc deficiency in these organelles appears to be associated with oxidative stress pathways of the Bcl-2 family with subsequent activation of caspase-3 [124], triggering apoptosis in B and T cells [126]. Experimental studies have demonstrated the implication of zinc in apoptosis in various organic tissues in sepsis and COVID-19 [127,128].…”

Section: Apoptosismentioning

confidence: 99%

The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis

Briassoulis,

Ilia

et al. 2023

Antioxidants

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Zinc is a structural component of proteins, functions as a catalytic co-factor in DNA synthesis and transcription of hundreds of enzymes, and has a regulatory role in protein–DNA interactions of zinc-finger proteins. For many years, zinc has been acknowledged for its anti-oxidative and anti-inflammatory functions. Furthermore, zinc is a potent inhibitor of caspases-3, -7, and -8, modulating the caspase-controlled apoptosis and necroptosis. In recent years, the immunomodulatory role of zinc in sepsis and COVID-19 has been investigated. Both sepsis and COVID-19 are related to various regulated cell death (RCD) pathways, including apoptosis and necroptosis. Lack of zinc may have a negative effect on many immune functions, such as oxidative burst, cytokine production, chemotaxis, degranulation, phagocytosis, and RCD. While plasma zinc concentrations decline swiftly during both sepsis and COVID-19, this reduction is primarily attributed to a redistribution process associated with the inflammatory response. In this response, hepatic metallothionein production increases in reaction to cytokine release, which is linked to inflammation, and this protein effectively captures and stores zinc in the liver. Multiple regulatory mechanisms come into play, influencing the uptake of zinc, the binding of zinc to blood albumin and red blood cells, as well as the buffering and modulation of cytosolic zinc levels. Decreased zinc levels are associated with increasing severity of organ dysfunction, prolonged hospital stay and increased mortality in septic and COVID-19 patients. Results of recent studies focusing on these topics are summarized and discussed in this narrative review. Existing evidence currently does not support pharmacological zinc supplementation in patients with sepsis or COVID-19. Complementation and repletion should follow current guidelines for micronutrients in critically ill patients. Further research investigating the pharmacological mechanism of zinc in programmed cell death caused by invasive infections and its therapeutic potential in sepsis and COVID-19 could be worthwhile.

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COVID-19 patients with high TNF/IFN-γ levels show hallmarks of PANoptosis, an inflammatory cell death

Cited by 13 publications

References 40 publications

IRF1 Mediates Growth Arrest and the Induction of a Secretory Phenotype in Alveolar Epithelial Cells in Response to Inflammatory Cytokines IFNγ/TNFα

IRF1 Mediates Growth Arrest and the Induction of a Secretory Phenotype in Alveolar Epithelial Cells in Response to Inflammatory Cytokines IFNγ/TNFα

PANoptosis: Mechanisms, biology, and role in disease

The Anti-Oxidative, Anti-Inflammatory, Anti-Apoptotic, and Anti-Necroptotic Role of Zinc in COVID-19 and Sepsis

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