Passive transfer of interferon-γ over-expressing macrophages enhances resistance of SCID mice to Mycobacterium tuberculosis infection

Pasula, Rajamouli; Martin, William J.; Kesavalu, Banu; Abdalla, Maher Y.; Britigan, Bradley E.

doi:10.1016/j.cyto.2017.02.009

Cited by 7 publications

(6 citation statements)

References 61 publications

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“…After recovery from CTX treatment for 12 hours, mice were infected with L. monocytogenes, and 18 h later samples were collected for further examinations (Fig.2C). In consistent with previous studies, L. monocytogene-induced clinical phenotype and mortality were relieved by transfusion of purified peritoneal macrophages 38,39 (Fig. 2D, S2C-D).…”

Section: Resultssupporting

confidence: 92%

“…Consistent with previous studies, L. monocytogene-induced clinical phenotype and mortality were relieved in the mice transferred with purified peritoneal macrophages (PMφ group; Figure 2F, S2C and S2D). 35,36 However, body weight was reduced, comprehensive clinical scoring was increased, and survival time was shortened in the mice transferred with CD36 + foamy macrophages compared with the control (FMφ group; Figure 2F, S2C and S2D). Furthermore, we showed that brain bacterial loads in mice transferred with CD36 + macrophages were significantly higher than those in mice transferred with purified peritoneal macrophages (Figure 2G).…”

Section: Cd36 + Foamy Macrophages Facilitate Transport Of Intracellul...mentioning

confidence: 99%

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Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

Sha,

Yang,

et al. 2024

Preprint

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Acute infection of the central nervous system is one of the most deadly diseases, but the mechanisms by which intracellular bacterial pathogens infiltrate the brain remain poorly understood. Phagocytic cells are usually recognized as the battlefield against intracellular bacteria; however, little is known about how the intracellular bacteria take advantage of infected phagocytes to access the brain. Here, we identify that a novel CD36+foamy macrophage subpopulation is participated in the brain penetration of intracellular bacteria. Biomechanical analysis reveals that the abundant protrusions and adhesion molecules confer significant resistance to the mechanical stress of blood flow, thereby providing more opportunities for foamy macrophages to adhere on the vascular endothelial surface during the neuroinvasion. By applying metabolomics analysis, we show that macrophage lipid metabolism is recalibrated during bacterial neuroinvasion, and β-hydroxybutyrate promotes the formation and survival of CD36+foamy macrophages. Altogether, our study uncovers a pathway by which intracellular bacteria hijack macrophages to achieve brain invasion and suggests that lipid metabolism may play a role in the prevention or resolution of bacterial neuroinvasion.

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Section: Resultssupporting

confidence: 92%

Section: Cd36 + Foamy Macrophages Facilitate Transport Of Intracellul...mentioning

confidence: 99%

Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

Sha,

Yang,

et al. 2024

Preprint

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“…Having considered cytokine responses, the expression of Arg1 and Nos2 and the secretion of NO were next addressed. In mice, the induction of iNOS is important for bactericidal NO production and subsequent killing of M. tuberculosis ( Flynn et al, 1993 ; Pasula et al, 2017 ). In turn, Arg1 directly impedes the bactericidal function of iNOS by sequestering the amino acid, arginine, which each enzyme uses to make their respective products: ornithine and NO.…”

Section: Resultsmentioning

confidence: 99%

Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses

Lundahl

Mitermite

Ryan

et al. 2022

eLife

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Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the 'classically activated' M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, 'alternatively activated' M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

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“…Having considered cytokine responses, the expression of Arg1 and Nos2 and the secretion of NO were next addressed. In mice, the induction of iNOS is important for bactericidal NO production and subsequent killing of M. tuberculosis (Flynn et al, 1993; Pasula, Martin, Kesavalu, Abdalla, & Britigan, 2017). In turn, Arg1 directly impedes the bactericidal function of iNOS by sequestering the amino acid, arginine, which each enzyme uses to make their respective products: ornithine and NO.…”

Section: Resultsmentioning

confidence: 99%

Macrophage Innate Training Induced by IL-4 and IL-13 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

Lundahl

Mitermite

Ryan

et al. 2021

Preprint

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Macrophages are key innate immune cells for determining the outcome of Mycobacterium tuberculosis infection. Polarization with IFNγ and LPS into the “classically activated” M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating the bacterium. By contrast, “alternatively activated” M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 counterintuitively induces protective innate memory against mycobacterial challenge. This was associated with enhanced pro-inflammatory cytokine responses and killing capacity. Moreover, despite this switch towards a phenotype that is more akin to classical activation, IL-4 trained macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4 trained macrophages. Lastly, this work identifies that IL-10 negatively regulates protective IL-4 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

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Passive transfer of interferon-γ over-expressing macrophages enhances resistance of SCID mice to Mycobacterium tuberculosis infection

Cited by 7 publications

References 61 publications

Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses

Macrophage Innate Training Induced by IL-4 and IL-13 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

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