Coactivation of TLR2 and TLR8 in Primary Human Monocytes Triggers a Distinct Inflammatory Signaling Response

Bösl, Korbinian; Giambelluca, Miriam S.; Haug, Markus; Bugge, Marit; Espevik, Terje; Kandasamy, Richard K.; Bergstrøm, Bjarte

doi:10.3389/fphys.2018.00618

Cited by 16 publications

(12 citation statements)

References 59 publications

(66 reference statements)

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“…B), confirming previous observations . Accordingly, we found that monocytes do accumulate IL‐12A mRNA upon TLR8 activation (data not shown), consistent with similar observations made by other groups . We also observed that CD14 + monocytes, unlike neutrophils (Fig.…”

Section: Resultssupporting

confidence: 93%

“…However, while in neutrophils, R848 was a more potent trigger of IL‐23 production than LPS and in monocytes both agonists had near equal potency. Moreover, CD14 + monocytes could also produce IL‐12, but, consistent with the literature, only if incubated with TLR8 agonists. These differences in cellular responses to different agonists clearly demonstrate that the results obtained with our highly pure neutrophil populations are not due to their potential contamination with CD14 + monocytes.…”

Section: Discussionsupporting

confidence: 88%

“…26 Accordingly, we found that monocytes do accumulate IL-12A mRNA upon TLR8 activation (data not shown), consistent with similar observations made by other groups. 30,31 We also observed that CD14 + monocytes, unlike neutrophils ( Fig. 3B), express high levels of IRF8, a transcription factor that, by interacting with IRF1 at the IL12A genomic locus, is essential for IL-12A transcription.…”

Section: Neutrophils Incubated With R848 Produce Il-23 But Not Il-12mentioning

confidence: 59%

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Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Tamassia

Arruda‐Silva

Wright

et al. 2019

Journal of Leukocyte Biology

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Human neutrophils contribute to the regulation of inflammation via the generation of a range of cytokines that affect all elements of the immune system. Here, we investigated their ability to express some of the members of the IL‐12 family after incubation with TLR8 agonists. Highly pure human neutrophils were thus incubated for up to 48 h with or without R848, or other TLR8 agonists, to then measure the expression levels of transcripts and proteins for IL‐12 family member subunits by RNA‐seq, reverse transcription quantitative PCR, and ELISA. We show a TLR8‐mediated inducible expression of IL‐12B and IL‐23A, but not IL‐12A, mRNA, which occurs via chromatin remodeling (as assessed by ChIP‐seq), and subsequent production of IL‐23 and IL‐12B, but no IL‐12, proteins. Induction of IL‐23 requires endogenous TNF‐α, as both mRNA and protein levels were blocked in TLR8‐activated neutrophils via a TNF‐α‐neutralizing Ab. We also show that supernatants from TLR8‐activated neutrophils, but not autologous monocytes, induce the differentiation of Th17 cells from naïve T cells in an IL‐23‐dependent fashion. This study unequivocally demonstrates that highly pure human neutrophils express and produce IL‐23, further supporting the key roles played by these cells in the important IL‐17/IL‐23 network and Th17 responses.

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Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 88%

Section: Neutrophils Incubated With R848 Produce Il-23 But Not Il-12mentioning

confidence: 59%

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Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Tamassia

Arruda‐Silva

Wright

et al. 2019

Journal of Leukocyte Biology

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“…This was largely dependent on TRIF and completely dependent on the capability to produce type I IFNs and on MyD88, proposedly through TLR2. It was also shown that co-stimulation of TLR2 and -8 inhibits IFNβ production by suppression of IRF5 [69]. This study proposed that activation of both TLRs shift T-cell differentiation from Th1 to Th17 through higher levels of IL-23 at the cost of IL-12p70 [69].…”

Section: Synergy Of Different Prrsmentioning

confidence: 84%

RNA Sensing of Mycobacterium tuberculosis and Its Impact on TB Vaccination Strategies

Burkert

Schumann

2020

Vaccines

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Tuberculosis (TB) is still an important global threat and although the causing organism has been discovered long ago, effective prevention strategies are lacking. Mycobacterium tuberculosis (MTB) is a unique pathogen with a complex host interaction. Understanding the immune responses upon infection with MTB is crucial for the development of new vaccination strategies and therapeutic targets for TB. Recently, it has been proposed that sensing bacterial nucleic acid in antigen-presenting cells via intracellular pattern recognition receptors (PRRs) is a central mechanism for initiating an effective host immune response. Here, we summarize key findings of the impact of mycobacterial RNA sensing for innate and adaptive host immunity after MTB infection, with emphasis on endosomal toll-like receptors (TLRs) and cytosolic sensors such as NLRP3 and RLRs, modulating T-cell differentiation through IL-12, IL-21, and type I interferons. Ultimately, these immunological pathways may impact immune memory and TB vaccine efficacy. The novel findings described here may change our current understanding of the host response to MTB and potentially impact clinical research, as well as future vaccination design. In this review, the current state of the art is summarized, and an outlook is given on how progress can be made.

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“…Several studies have focused on the genome-wide effects of TLR ligands on hematopoietic cells such as monocytes [54]. In the current study, we aimed to determine the specific roles of DUSPs and PKs in TLR4 signaling.…”

Section: Expression Landscape and Signaling Dynamics Of Dusps And Kinmentioning

confidence: 99%

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

Subbannayya

Pinto

Bösl

et al. 2019

Preprint

Self Cite

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Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focused on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSPmediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study has the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.

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Coactivation of TLR2 and TLR8 in Primary Human Monocytes Triggers a Distinct Inflammatory Signaling Response

Cited by 16 publications

References 59 publications

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

RNA Sensing of Mycobacterium tuberculosis and Its Impact on TB Vaccination Strategies

Dynamics of dual specificity phosphatases and their interplay with protein kinases in immune signaling

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