Primary macrophages and J774 cells respond differently to infection with Mycobacterium tuberculosis

Andreu, Núria; Phelan, Jody; Sessions, Paola Flórez de; Cliff, Jacqueline M.; Clark, Taane G.; Hibberd, Martin L.

doi:10.1038/srep42225

Cited by 88 publications

(90 citation statements)

References 75 publications

(83 reference statements)

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“…Other studies showed that Mtb-infected fibroblasts die from necroptosis via RIPK1-RIPK3-MLKL in a TNF-α-dependent manner (Butler et al, 2017) and that MLKL does not appear to be activated in Mtb-infected bone marrow-derived or J774.1 mouse macrophages (Butler et al, 2017; Stutz et al, 2018). These apparent discrepancies may result from cell-type-specific differences (Andreu et al, 2017). …”

Section: Discussionmentioning

confidence: 99%

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

et al. 2018

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SUMMARY Mycobacterium tuberculosis (Mtb) kills infected macrophages by inhibiting apoptosis and promoting necrosis. The tuberculosis necrotizing toxin (TNT) is a secreted nicotinamide adenine dinucleotide (NAD+) glycohydrolase that induces necrosis in infected macrophages. Here, we show that NAD+ depletion by TNT activates RIPK3 and MLKL, key mediators of necroptosis. Notably, Mtb bypasses the canonical necroptosis pathway since neither TNF-α nor RIPK1 are required for macrophage death. Macrophage necroptosis is associated with depolarized mitochondria and impaired ATP synthesis, known hallmarks of Mtb-induced cell death. These results identify TNT as the main trigger of necroptosis in Mtb-infected macrophages. Surprisingly, NAD+ depletion itself was sufficient to trigger necroptosis in a RIPK3- and MLKL-dependent manner by inhibiting the NAD+ salvage pathway in THP-1 cells or by TNT expression in Jurkat T cells. These findings suggest avenues for host-directed therapies to treat tuberculosis and other infectious and age-related diseases in which NAD+ deficiency is a pathological factor.

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Section: Discussionmentioning

confidence: 99%

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

et al. 2018

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“…S1 and Table S1). This significant genetic response derived from the collection/culture times for uninfected macrophages is well documented (28).…”

Section: Figmentioning

confidence: 93%

Conservation of Intracellular Pathogenic Strategy among Distantly Related Cryptococcal Species

Freij

Rodriguez

et al. 2018

Infect Immun

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The genus includes several species pathogenic for humans. Until recently, the two major pathogenic species were recognized to be and We compared the interaction of murine macrophages with three species complex strains (WM179, R265, and WM161, representing molecular types VGI, VGIIa, and VGIII, respectively) and one species complex strain (H99, molecular type VNI) to ascertain similarities and differences in the yeast intracellular pathogenic strategy. The parameters analyzed included nonlytic exocytosis frequency, phagolysosomal pH, intracellular capsular growth, phagolysosomal membrane permeabilization, and macrophage transcriptional response, assessed using time-lapse microscopy, fluorescence microscopy, flow cytometry, and gene expression microarray analysis. The most striking result was that the intracellular pathogenic strategies of and species complex strains were qualitatively similar, despite the species having separated an estimated 100 million years ago. Macrophages exhibited a leaky phagolysosomal membrane phenotype and nonlytic exocytosis when infected with either or Conservation of the intracellular strategy among species that separated long ago suggests that it is ancient and possibly maintained by similar selection pressures through eons.

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“…Selecting cell models reflecting appropriately the heterogeneity of tissue-specific macrophages is particularly challenging since macrophage models for in vitro studies are affected by several limits (Chanput et al 2014;Andreu et al 2017). Macrophages in fact can be best investigated using primary cells.…”

Section: Introductionmentioning

confidence: 99%

“…Macrophages in fact can be best investigated using primary cells. This is because in many cases the genetic background of transformed macrophage cell lines is not well defined, and transformed lines may not reflect well the phenotype of the original macrophage type (Pan et al 2009;Chanput et al 2014;Andreu et al 2017). Nevertheless, given the limited availability of primary macrophages, to have access to sufficient quantities of cells, in vitro studies often use immortalized macrophage cell lines [a classic example being differentiated human THP-1 monocytes (Lunov et al 2011)], even if they are not always optimal for this purpose.…”

Section: Introductionmentioning

confidence: 99%

Time-resolved characterization of the mechanisms of toxicity induced by silica and amino-modified polystyrene on alveolar-like macrophages

et al. 2019

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Macrophages play a major role in the removal of foreign materials, including nano-sized materials, such as nanomedicines and other nanoparticles, which they accumulate very efficiently. Because of this, it is recognized that for a safe development of nanotechnologies and nanomedicine, it is essential to investigate potential effects induced by nano-sized materials on macrophages. To this aim, in this work, a recently established model of primary murine alveolar-like macrophages was used to investigate macrophage responses to two well-known nanoparticle models: 50 nm amino-modified polystyrene, known to induce cell death via lysosomal damage and apoptosis in different cell types, and 50 nm silica nanoparticles, which are generally considered non-toxic. Then, a time-resolved study was performed to characterize in detail the response of the macrophages following exposure to the two nanoparticles. As expected, exposure to the amino-modified polystyrene led to cell death, but surprisingly no lysosomal swelling or apoptosis were detected. On the contrary, a peculiar mitochondrial membrane hyperpolarization was observed, accompanied by endoplasmic reticulum stress (ER stress), increased cellular reactive oxygen species (ROS) and changes of metabolic activity, ultimately leading to cell death. Strong toxic responses were observed also after exposure to silica, which included mitochondrial ROS production, mitochondrial depolarization and cell death by apoptosis. Overall, these results showed that exposure to the two nanoparticles led to a very different series of intracellular events, suggesting that the macrophages responded differently to the two nanoparticle models. Similar time-resolved studies are required to characterize the response of macrophages to nanoparticles, as a key parameter in nanosafety assessment.

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Primary macrophages and J774 cells respond differently to infection with Mycobacterium tuberculosis

Cited by 88 publications

References 75 publications

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

Conservation of Intracellular Pathogenic Strategy among Distantly Related Cryptococcal Species

Time-resolved characterization of the mechanisms of toxicity induced by silica and amino-modified polystyrene on alveolar-like macrophages

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