Differences in the repertoire, regulation and function of Toll-like Receptors and inflammasome-forming Nod-like Receptors between human and mouse

Ariffin, Juliana K.; Sweet, Matthew J.

doi:10.1016/j.mib.2013.03.002

Cited by 42 publications

(31 citation statements)

References 56 publications

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“…However, studies on the impacts of HDACi on host immunity have primarily utilized mouse models or mouse cells, and effects on host defense in humans have not been intensively investigated. Although human and mouse innate immune responses are broadly conserved, some phenotypic differences, divergence in gene repertoires, and differential regulation of orthologous genes have been noted between humans and mice (20)(21)(22)(23). Here we report that, while long-term treatment of human macrophages with HDACi impairs the phagocytic capacity of human macrophages, acute treatment with HDACi at the time of bacterial infection actually enhances mitochondrial ROS (mitoROS) production from these cells, which correlates with increased antibacterial responses.…”

mentioning

confidence: 78%

“…Although some mouse studies have suggested that HDACi may compromise host defense against bacterial and fungal pathogens (14,19), very few studies have examined the regulation of human macrophage antimicrobial responses by HDACi. Given some differences in innate immune pathways between human and mouse, particularly in relation to host defense (20,22), we examined the effects of HDACi on human macrophage responses to bacterial challenge in this study.…”

Section: Discussionmentioning

confidence: 99%

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Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Ariffin

Gupta

Kapétanovic

et al. 2016

Antimicrob Agents Chemother

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Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge with Salmonella enterica serovar Typhimurium or Escherichia coli results in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellular S. Typhimurium and E. coli. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.

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mentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Ariffin

Gupta

Kapétanovic

et al. 2016

Antimicrob Agents Chemother

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“…Some interpretations of human disease mechanisms have been made based on extrapolating from observations of mouse studies. However, there are important differences in LPS-induced TLR4 signaling between humans and mice (20)(21)(22), necessitating careful assessment of C5aR/TLR4 crosstalk in human cells.…”

mentioning

confidence: 99%

Inflammatory Responses Induced by Lipopolysaccharide Are Amplified in Primary Human Monocytes but Suppressed in Macrophages by Complement Protein C5a

Seow

Lim

Iyer

et al. 2013

The Journal of Immunology

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Monocytes and macrophages are important innate immune cells equipped with danger-sensing receptors, including complement and Toll-like receptors. Complement protein C5a, acting via C5aR, is shown in this study to differentially modulate LPS-induced inflammatory responses in primary human monocytes versus macrophages. Whereas C5a enhanced secretion of LPS-induced IL-6 and TNF from primary human monocytes, C5a inhibited these responses while increasing IL-10 secretion in donor-matched human monocyte-derived macrophages differentiated by GM-CSF or M-CSF. Gαi/c-Raf/MEK/ERK signaling induced by C5a was amplified in macrophages but not in monocytes by LPS. Accordingly, the Gαi inhibitor pertussis toxin and MEK inhibitor U0126 blocked C5a inhibition of LPS-induced IL-6 and TNF production from macrophages. This synergy was independent of IL-10, PI3K, p38, JNK, and the differentiating agent. Furthermore, C5a did not inhibit IL-6 production from macrophages induced by other TLR agonists that are selective for Toll/IL-1R domain–containing adapter inducing IFN-β (polyinosinic-polycytidylic acid) or MyD88 (imiquimod), demonstrating selectivity for C5a regulation of LPS responses. Finally, suppression of proinflammatory cytokines IL-6 and TNF in macrophages did not compromise antimicrobial activity; instead, C5a enhanced clearance of the Gram-negative bacterial pathogen Salmonella enterica serovar Typhimurium from macrophages. C5aR is thus a regulatory switch that modulates TLR4 signaling via the Gαi/c-Raf/MEK/ERK signaling axis in human macrophages but not monocytes. The differential effects of C5a are consistent with amplifying monocyte proinflammatory responses to systemic danger signals, but attenuating macrophage cytokine responses (without compromising microbicidal activity), thereby restraining inflammatory responses to localized infections.

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“…Although inbred strains of mice show different vaccine responses, for example, it is well known that BALB/c tend to produce high antibody levels dominated by Th2 cells (helper T cell type 2), whereas C57BL/6 mice tend to produce lower antibody responses but better Th1-dominated responses [55]. Most important, there are significant differences in immune response genes between humans and rodents, from the different roles of specific TLR and other activation and suppression genes, to the absence of some genes in either species [56,57]. As a result, the genetic influences on immune responses in rodents are unreliable indicators of human responses, especially at the level of individual gene polymorphisms.…”

Section: Cocaine Vaccine Trialsmentioning

confidence: 99%

The future potential for cocaine vaccines

Orson

Wang

Brimijoin

et al. 2014

Expert Opinion on Biological Therapy

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Introduction Addiction to cocaine is a major problem around the world, but especially in developed countries where the combination of wealth and user demand has created terrible social problems. Although only some users become truly addicted, those who are often succumb to a downward spiral in their lives from which it is very difficult to escape. From the medical perspective, the lack of effective and safe, non-addictive therapeutics has instigated efforts to develop alternative approaches for treatment, including anticocaine vaccines designed to block cocaine’s pharmacodynamic effects. Areas covered This paper discusses the implications of cocaine pharmacokinetics for robust vaccine antibody responses, the results of human vaccine clinical trials, new developments in animal models for vaccine evaluation, alternative vaccine formulations and complementary therapy to enhance anticocaine effectiveness. Expert opinion Robust anti-cocaine antibody responses are required for benefit to cocaine abusers, but since any reasonably achievable antibody level can be overcome with higher drug doses, sufficient motivation to discontinue use is also essential so that the relative barrier to cocaine effects will be appropriate for each individual. Combining a vaccine with achievable levels of an enzyme to hydrolyze cocaine to inactive metabolites, however, may substantially increase the blockade and improve treatment outcomes.

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Differences in the repertoire, regulation and function of Toll-like Receptors and inflammasome-forming Nod-like Receptors between human and mouse

Cited by 42 publications

References 56 publications

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

Inflammatory Responses Induced by Lipopolysaccharide Are Amplified in Primary Human Monocytes but Suppressed in Macrophages by Complement Protein C5a

The future potential for cocaine vaccines

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