Purinergic Signaling to Terminate TLR Responses in Macrophages

Hamidzadeh, Kajal; Mosser, David M.

doi:10.3389/fimmu.2016.00074

Cited by 33 publications

(30 citation statements)

References 57 publications

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“…Interestingly, IL-21 is known to upregulate CD73 on B and T cells [ 14 ]. Adenosine generated by CD73 has been shown to modulate cytokine production in macrophages [ 28 ]. It is possible that altered cytokine production lies at the heart of the isotype switch delay in CD73-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

CD73-A2a adenosine receptor axis promotes innate B cell antibody responses to pneumococcal polysaccharide vaccination

et al. 2018

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Many individuals at risk of streptococcal infection respond poorly to the pneumococcal polysaccharide vaccine Pneumovax 23. Identification of actionable pathways able to enhance Pneumovax responsiveness is highly relevant. We investigated the contribution of the extracellular adenosine pathway regulated by the ecto-nucleotidase CD73 in Pneumovax-induced antibody responses. Using gene-targeted mice, we demonstrated that CD73-or A2a adenosine receptor deficiency significantly delayed isotype switching. Nevertheless, CD73- or A2aR- deficient adult mice ultimately produced antigen-specific IgG3 and controlled Streptococcus pneumoniae infection as efficiently as wild type (WT) mice. Compared to adults, young WT mice failed to control S. pneumoniae infection after vaccination and this was associated with lower levels of CD73 on innate B cells. We hypothesized that pharmacological activation of A2a receptor may improve Pneumovax 23 immunization in young WT mice. Remarkably, administration of the A2a adenosine receptor agonist CGS 21680 significantly increased IgG3 responses and significantly enhanced survival after S. pneumoniae challenge. Our study thus suggests that pharmacological activation of the A2a adenosine receptor could improve the efficacy of Pneumovax 23 vaccination in individuals at risk of streptococcal infection.

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Section: Discussionmentioning

confidence: 99%

CD73-A2a adenosine receptor axis promotes innate B cell antibody responses to pneumococcal polysaccharide vaccination

et al. 2018

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“…A second plausible explanation would be the difference in ectoenzyme CD39 expression, responsible for the breakdown of ATP into ADP and AMP. Although monocytes and macrophages are reported to express ectoenzymes CD39 and CD73, there has been no direct comparison on the level of their expression [ 20 , 21 ]. On the other hand, the difference in decay kinetics of the two cells in response to ATP stimulation may be a result of the different buffering capacity of Ca 2+ of the two cells.…”

Section: Discussionmentioning

confidence: 99%

P2X4 Receptor-Dependent Ca2+ Influx in Model Human Monocytes and Macrophages

Layhadi

Fountain

2017

IJMS

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Monocytes and macrophages express a repertoire of cell surface P2 receptors for adenosine 5′-triphosphate (ATP) a damage-associated molecular pattern molecule (DAMP), which are capable of raising cytoplasmic calcium when activated. This is achieved either through direct permeation (ionotropic P2X receptors) or by mobilizing intracellular calcium stores (metabotropic P2Y receptors). Here, a side-by-side comparison to investigate the contribution of P2X4 receptor activation in ATP-evoked calcium responses in model human monocytes and macrophages was performed. The expression of P2X1, P2X4, P2X5 and P2X7 was confirmed by qRT-PCR and immunocytochemistry in both model monocyte and macrophage. ATP evoked a concentration-dependent increase in intracellular calcium in both THP-1 monocyte and macrophages. The sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thasigargin (Tg) responses to the maximal ATP concentration (100 μM) in THP-1 monocytes, and responses in macrophage were significantly attenuated. Tg-resistant ATP-evoked calcium responses in the model macrophage were dependent on extracellular calcium, suggesting a requirement for calcium influx. Ivermectin (IVM) potentiated the magnitude of Tg-resistant component and slowed the decay of response in the model macrophage. The Tg-resistant component was attenuated by P2X4 antagonists 5-BDBD and PSB-12062 but not by the P2X1 antagonist Ro0437626 or the P2X7 antagonist A438079. shRNA-mediated P2X4 knockdown resulted in a significant reduction in Tg-resistant ATP-evoked calcium response as well as reduced sensitivities towards P2X4-specific pharmacological tools, IVM and PSB-12062. Inhibition of endocytosis with dynasore significantly reduced the magnitude of Tg-resistant component but substantially slowed decay response. Inhibition of calcium-dependent exocytosis with vacuolin-1 had no effect on the Tg-resistant component. These pharmacological data suggest that P2X4 receptor activation contributed significantly towards the ionotropic calcium response evoked by ATP of the model human macrophage.

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“…However, there are reports that such a high concentration of gentamicin penetrates HeLa cells, reaching c. 90% of the extracellular concentration after incubation for 72 h. The M1, or proinflammatory, macrophage phenotype is characterized by high levels of proinflammatory cytokines and reactive nitrogen and oxygen intermediates, the promotion of a Th1 response, and strong microbicidal and tumoricidal activity. Phagocytosis is the first step in the macrophage response to invading microorganisms and activation of phagocytosis enhances innate immune responses ( 33 ). Phagocytosis by macrophages was increased by M. alba L. treatment in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Activation of macrophage mediated host defense against Salmonella typhimurium by Morus alba L.

Chang¹,

Koo²,

Lee³

et al. 2018

Food & Nutrition Research

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BackgroundThe innate immune system plays a crucial role in the initiation and subsequent direction of adaptive immune responses, as well as in the removal of pathogens that have been targeted by an adaptive immune response.ObjectiveMorus alba L. was reported to have immunostimulatory properties that might protect against infectious diseases. However, this possibility has not yet been explored. The present study investigated the protective and immune-enhancing ability of M. alba L. against infectious disease and the mechanisms involved.DesignTo investigate the immune-enhancing effects of M. alba L., we used a bacterial infection model.Results and discussionsThe lifespan of mice infected with a lethal dose of Salmonella typhimurium (1 × 107 colony forming units – CFU) was significantly extended when they were administered M. alba L. Furthermore, M. alba L. activated macrophages, monocytes, and neutrophils and induced Th1 cytokines (IL-12, IFN-γ, TNF-α) in mice infected with a sublethal dose (1 × 105 CFU) of S. typhimurium. M. alba L. significantly stimulated the uptake of bacteria into peritoneal macrophages as indicated by increased phagocytosis. Peritoneal macrophages derived from C3H/HeJ mice significantly inhibited M. alba L. induced NO production and TNF-α secretion compared with peritoneal macrophages derived from C3H/HeN mice.ConclusionsThese results suggest that the innate immune activity of M. alba L. against bacterial infection in mice occurs through activation of the TLR4 signaling pathway.

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Purinergic Signaling to Terminate TLR Responses in Macrophages

Cited by 33 publications

References 57 publications

CD73-A2a adenosine receptor axis promotes innate B cell antibody responses to pneumococcal polysaccharide vaccination

CD73-A2a adenosine receptor axis promotes innate B cell antibody responses to pneumococcal polysaccharide vaccination

P2X4 Receptor-Dependent Ca2+ Influx in Model Human Monocytes and Macrophages

Activation of macrophage mediated host defense against Salmonella typhimurium by Morus alba L.

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