Tnf dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species
Open accessAbstract
Tumor necrosis factor (TNF) constitutes a critical host defense against tuberculosis, but its excess is also implicated in tuberculosis pathogenesis in zebrafish and humans. Using the zebrafish, we elucidate the pathways by which TNF mediates tuberculosis pathogenesis. TNF excess induces mitochondrial reactive oxygen species (ROS) in infected macrophages through RIP1-RIP3-dependent pathways. While initially increasing macrophage microbicidal activity, ROS rapidly induce programmed necrosis (necroptosis) and release mycobacteria into the growth-permissive extracellular milieu. TNF-induced necroptosis occurs through two pathways: modulation of mitochondrial cyclophilin D, implicated in mitochondrial permeability transition pore formation, and acid sphingomyelinase-mediated ceramide production. Combined genetic blockade of cyclophilin D and acid sphingomyelinase renders the high TNF state hyperresistant by preventing macrophage necrosis while preserving increased microbicidal activity. Similarly, the cyclophilin D-inhibiting drug alisporivir and the acid sphingomyelinase-inactivating drug, desipramine, synergize to reverse susceptibility, suggesting the therapeutic potential of these orally active drugs against tuberculosis and possibly other TNF-mediated diseases.
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Membrane-disrupting damage of mitochondria or opening of the mPTP is necessary for matrix mtROS release into the cytosol.
“Membrane-disrupting damage of mitochondria or opening of the mitochondrial permeability transition pore (mPTP) is necessary for matrix mtROS release into the cytosol [127,128,129,130,131].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [129]
Matrix mtROS cannot escape from intact mitochondria.
“matrix mtROS cannot escape from intact mitochondria, which was confirmed for isolated mitochondria as well as in cells [127,128,129].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [129]
Early cytosolic mtROS released by opened mPTP led to killing of Mtb, but later resulted in necroptosis of macrophages.
“The early effect of cytosolic mtROS released by the opened mPTP led to killing of Mtb, but later on it resulted in necroptosis of macrophages [129].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [129]
TNF priming induces production of antibacterial matrix mtROS by two converging signaling pathways: RIPK1-RIPK3-mediated calcium overload and mPTP opening via RIPK1, RIPK3 and MLKL.
“Priming with TNF, however, induced production of antibacterial matrix mtROS by two converging signaling pathways. Firstly, TNF mediated induction of matrix mtROS production by ryanoid-receptor-receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-RIPK3-mediated calcium overload of mitochondria [257]. Secondly, since matrix mtROS cannot escape the matrix of intact mitochondria [127,128,129”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [129]
Mtb infection alone was not sufficient to increase total cellular ROS levels or to induce matrix mtROS production in zebrafish macrophages.
“Mtb infection alone was not sufficient to increase total cellular ROS levels or to induce matrix mtROS production in zebrafish macrophages.”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [129]
From intact mitochondria, matrix mtROS cannot reach the cytosol or other compartments.
“Moreover, from intact mitochondria matrix mtROS cannot reach the cytosol or other compartments [38,122,127,129,131,310].”
From Functions of ROS in Macrophages and Antimicrobial Immunity (2021) · cites this paper as [129]
Macrophage necroptosis impairs granuloma formation and compromises resistance to Mycobacteria infection in zebrafish.
“The recent finding that Mø necroptosis impairs granuloma formation and compromises resistance to Mycobacteria infection in zebrafish supports this notion [174].”
From The Iron age of host–microbe interactions (2015) · cites this paper as [174]
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- Authors
- Roca, F. J., & Ramakrishnan, L.
- Affiliations
- University of Washington (US)
- Corresponding author
- Ramakrishnan, Lalita
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 153
- Issue
- 3
- Pages
- 521-534
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3790588
- OpenAlex
- W2129443010
- Cited by
- 592
- References
- 72
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 47 · 2023: 32 · 2022: 45 · 2021: 54 · 2020: 59 · 2019: 36 · 2018: 37 · 2017: 43 · 2016: 45 · 2015: 48 · 2014: 60 · 2013: 22
- FWCI
- 42.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Hispana (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DP1OD006782)
- National Institute of Allergy and Infectious Diseases (R01AI036396, R37AI054503)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TNF-α, tuberculosis, mycobacteria, mitochondrial reactive oxygen species, necroptosis, cyclophilin D, mitochondrial permeability transition pore, acid sphingomyelinase, ceramide, macrophage microbicidal activity, alisporivir, desipramine, drug synergy, host-pathogen interaction, zebrafish model
- MeSH terms
- Peptidyl-Prolyl Isomerase F, Animals, Disease Models, Animal, Disease Susceptibility, Humans, Macrophages, Mitochondria, Mycobacterium, Necrosis, Tuberculosis, Zebrafish, Reactive Oxygen Species, Cyclophilins, Tumor Necrosis Factors, Receptor-Interacting Protein Serine-Threonine Kinases, Metabolic Networks and Pathways
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