TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species

Roca Soler, Francisco José; Ramakrishnan, Lalita

Publication:
TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species

dc.contributor.author	Roca Soler, Francisco José
dc.contributor.author	Ramakrishnan, Lalita
dc.contributor.department	Bioquímica y Biología Molecular B e Inmunología
dc.date.accessioned	2026-02-25T16:21:03Z
dc.date.available	2026-02-25T16:21:03Z
dc.date.copyright	© 2013 Elsevier Inc.
dc.date.issued	2013-04-11
dc.description.abstract	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.
dc.format	application/pdf
dc.format.extent	14
dc.identifier.citation	Cell 153, 521–534, April 25, 2013
dc.identifier.doi	https://doi.org/10.1016/j.cell.2013.03.022
dc.identifier.eissn	1097-4172
dc.identifier.issn	0092-8674
dc.identifier.uri	http://hdl.handle.net/10201/213581
dc.language	eng
dc.publisher	Cell Press
dc.relation	Funded by grants from the NIH and the NWRCE for Biodefense and Emerging Infectious Diseases Research (L.R.), and a postdoctoral fellowship from the educational ministry of Spain (F.J.R). L.R. is a recipient of the NIH Director’s Pioneer Award
dc.relation.publisherversion	https://www.sciencedirect.com/science/article/pii/S0092867413003449
dc.rights.accessRights	info:eu-repo/semantics/restrictedAccess
dc.subject.ods	Objetivo 3: Salud
dc.title	TNF dually mediates resistance and susceptibility to mycobacteria via mitochondrial reactive oxygen species
dc.type	info:eu-repo/semantics/article
dc.type.version	info:eu-repo/semantics/publishedVersion
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