ArticleCell death and differentiation2018
Necroptotic signaling is primed in Mycobacterium tuberculosis-infected macrophages, but its pathophysiological consequence in disease is restricted.
Article in Cell death and differentiation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- Pooled it
- Article
- Applications of humanized mice inMolecular medicine reports · 2026Review
- Characterization of programmed cell death pathways activated in Mycobacterium tuberculosis-infected human macrophages.Cell death discovery · 2026Article
- Research progress in PANoptosis mechanisms and their interplay with tuberculosis.Frontiers in cellular and infection microbiology · 2026Review
- Cell death pathways in response toInfection and immunity · 2025Review
- Article
- A bacterial effector manipulates host lysosomal protease activity-dependent plasticity in cell death modalities to facilitate infection.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Targeting necroptosis: a promising avenue for respiratory disease treatment.Cell communication and signaling : CCS · 2024Review
- Humanized Mouse Models of Bacterial Infections.Antibiotics (Basel, Switzerland) · 2024Review
- Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity.Nature reviews. Cancer · 2024Review
- Mycobacterium ulcerans challenge strain selection for a Buruli ulcer controlled human infection model.PLoS neglected tropical diseases · 2024Article
- Metabolic changes enhance necroptosis of type 2 diabetes mellitus mice infected with Mycobacterium tuberculosis.PLoS pathogens · 2024Article
- Necroptosis does not drive disease pathogenesis in a mouse infective model of SARS-CoV-2 in vivo.Cell death & disease · 2024Article
- Review
- Necroptosis in bacterial infections.Frontiers in immunology · 2024Review
- Identification and validation of a novel necroptosis-related molecular signature to evaluate prognosis and immune features in breast cancer.Apoptosis : an international journal on programmed cell death · 2023Article
- Association between High Interferon-Gamma Production in Avian Tuberculin-Stimulated Blood fromMicroorganisms · 2023Article
- Virulence Factors ofPathogens (Basel, Switzerland) · 2023Review
- Review
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mixed lineage kinase domain-like (MLKL)-dependent necroptosis is thought to be implicated in the death of mycobacteria-infected macrophages, reportedly allowing escape and dissemination of the microorganism. Given the consequent interest in developing inhibitors of necroptosis to treat Mycobacterium tuberculosis (Mtb) infection, we used human pharmacologic and murine genetic models to definitively establish the pathophysiological role of necroptosis in Mtb infection. We observed that Mtb infection of macrophages remodeled the intracellular signaling landscape by upregulating MLKL, TNFR1, and ZBP1, whilst downregulating cIAP1, thereby establishing a strong pro-necroptotic milieu. However, blocking necroptosis either by deleting Mlkl or inhibiting RIPK1 had no effect on the survival of infected human or murine macrophages. Consistent with this, MLKL-deficiency or treatment of humanized mice with the RIPK1 inhibitor Nec-1s did not impact on disease outcomes in vivo, with mice displaying lung histopathology and bacterial burdens indistinguishable from controls. Therefore, although the necroptotic pathway is primed by Mtb infection, macrophage necroptosis is ultimately restricted to mitigate disease pathogenesis. We identified cFLIP upregulation that may promote caspase 8-mediated degradation of CYLD, and other necrosome components, as a possible mechanism abrogating Mtb's capacity to coopt necroptotic signaling. Variability in the capacity of these mechanisms to interfere with necroptosis may influence disease severity and could explain the heterogeneity of Mtb infection and disease.
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