Illuminating the Black Box of TNF Action in Tuberculous Granulomas

Miller, Elizabeth A.; Ernst, Joel D.

doi:10.1016/j.immuni.2008.07.003

Cited by 17 publications

(11 citation statements)

References 10 publications

(24 reference statements)

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“…The cytokine TNF is essential for host defense against mycobacteria and anti-TNF therapy may lead to disorganization of human tuberculous granuloma resulting in reactivation of latent tuberculosis [3], [16]–[19]. Since activation of the TCRαβ in macrophages results in CCL2 release, a key factor in granuloma formation, we examined whether TNFinhibition has a direct impact on the expression of the macrophage-TCRαβ.…”

Section: Resultsmentioning

confidence: 99%

“…The disease is caused by mycobacteria that are efficiently contained by macrophages in highly organized immune structures, the tuberculous granulomas. Ample evidence indicates that the generation and maintenance of tuberculous granulomas require TNF [3], [4]. Moreover, reactivation of the disease by therapeutic TNF blockade is associated with disruption of the granuloma architecture that ultimately leads to spreading of the mycobacteria into the surrounding tissue [5].…”

Section: Introductionmentioning

confidence: 99%

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A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

et al. 2011

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Macrophages play a central role in host defense against mycobacterial infection and anti- TNF therapy is associated with granuloma disorganization and reactivation of tuberculosis in humans. Here, we provide evidence for the presence of a T cell receptor (TCR) αβ based recombinatorial immune receptor in subpopulations of human and mouse monocytes and macrophages. In vitro, we find that the macrophage-TCRαβ induces the release of CCL2 and modulates phagocytosis. TNF blockade suppresses macrophage-TCRαβ expression. Infection of macrophages from healthy individuals with mycobacteria triggers formation of clusters that express restricted TCR Vβ repertoires. In vivo, TCRαβ bearing macrophages abundantly accumulate at the inner host-pathogen contact zone of caseous granulomas from patients with lung tuberculosis. In chimeric mouse models, deletion of the variable macrophage-TCRαβ or TNF is associated with structurally compromised granulomas of pulmonary tuberculosis even in the presence of intact T cells. These results uncover a TNF-regulated recombinatorial immune receptor in monocytes/macrophages and demonstrate its implication in granuloma formation in tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

et al. 2011

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“…Rather its primary role in early protection appears to be to restrict mycobacterial growth within macrophages. Indeed, lack of TNF signaling results in accelerated granuloma formation, presumably because of an increased proportional increase in RD1 within the inciting infected macrophages (Clay et al, 2008; Miller and Ernst, 2008). Infection with ΔRD1 Mm results in attenuated infection with poor granuloma formation even in the absence of TNF signaling, further confirming the lack of involvement of this prime candidate in RD1-mediated granuloma formation.…”

Section: Discussionmentioning

confidence: 99%

The Role of the Granuloma in Expansion and Dissemination of Early Tuberculous Infection

Davis

Ramakrishnan

2009

Cell

773

761

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SUMMARY Granulomas, organized aggregates of immune cells, form in response to persistent stimuli and are hallmarks of tuberculosis. Tuberculous granulomas have long been considered host-protective structures formed to contain infection. However, work in zebrafish infected with Mycobacterium marinum suggests that granulomas contribute to early bacterial growth. Here we use quantitative intravital microscopy to reveal distinct steps of granuloma formation and assess their consequence for infection. Intracellular mycobacteria use theESX-1/RD1virulence locus to induce recruitment of new macrophages to, and their rapid movement within, nascent granulomas. This motility enables multiple arriving macrophages to efficiently find and phagocytose infected macrophages undergoing apoptosis, leading to rapid, iterative expansion of infected macrophages and thereby bacterial numbers. The primary granuloma then seeds secondary granulomas via egress of infected macrophages. Our direct observations provide insight into how pathogenic mycobacteria exploit the granuloma during the innate immune phase for local expansion and systemic dissemination.

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“…This is of specific interest because of the swift reactivation of tuberculosis after TNF-␣-blocking therapy (23). TNF-␣ has a paramount role in granuloma formation and maintenance (24) and contributes importantly to the balance of pro-and anti-inflammatory cytokines that determines the success of mycobacterial control (25).…”

Section: Discussionmentioning

confidence: 99%

Low Induction of Proinflammatory Cytokines Parallels Evolutionary Success of Modern Strains within the Mycobacterium tuberculosis Beijing Genotype

Laarhoven¹,

Mandemakers

Kleinnijenhuis³

et al. 2013

Infect Immun

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Illuminating the Black Box of TNF Action in Tuberculous Granulomas

Abstract: TNF clearly contributes to immunity to intracellular pathogens, but how it does so is incompletely understood. In this issue of Immunity, Clay et al. (2008) provide unique insights, using intravital microscopy and the zebrafish-embryo model of tuberculosis.

Cited by 17 publications

References 10 publications

A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

A TNF-Regulated Recombinatorial Macrophage Immune Receptor Implicated in Granuloma Formation in Tuberculosis

The Role of the Granuloma in Expansion and Dissemination of Early Tuberculous Infection

Low Induction of Proinflammatory Cytokines Parallels Evolutionary Success of Modern Strains within the Mycobacterium tuberculosis Beijing Genotype

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