Cefoxitin treatment of MRSA leads to a shift in the IL-12/IL-23 production pattern in dendritic cells by a mechanism involving changes in the MAPK signaling

ABSTRACT Bordetella bronchiseptica utilizes a type III secretion system (TTSS) to establish a persistent infection of the murine respiratory tract. Previous studies have shown that the Bordetella TTSS mediated cytotoxicity in different cell types, inhibition of NF-κB in epithelial cells, and differentiation of dendritic cells into a semimature state. Here we demonstrate modulation of mitogen-activated protein kinase (MAPK) signaling pathways and altered cytokine production in macrophages and dendritic cells by the Bordetella TTSS. In macrophages, the MAPKs ERK and p38 were downregulated. This resulted in attenuated production of interleukin- (IL-)6 and IL-10. In contrast, the Th-1-polarizing cytokine IL-12 was produced at very low levels and remained unmodulated by the Bordetella TTSS. In dendritic cells, ERK was transiently activated, but this failed to alter cytokine profiles. These results suggest that the Bordetella TTSS modulates antigen-presenting cells in a cell type-specific manner and the secretion of high levels of IL-6 and IL-10 by macrophages might be important for pathogen clearance.

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Convergent Met and voltage-gated Ca2+ channel signaling on Ras-Erk MAPK drives migratory activation of dendritic cells parasitized by Toxoplasma gondii

10.1101/2020.01.08.898197 ◽

2020 ◽

Author(s):

Einar B. Ólafsson ◽

Arne L. ten Hoeve ◽

Xiaoze Li Wang ◽

Linda Westermark ◽

Manuel Varas-Godoy ◽

...

Keyword(s):

Dendritic Cells ◽

Toxoplasma Gondii ◽

Immune Cell ◽

Mapk Signaling ◽

Infection Model ◽

Multiple Cancer ◽

Voltage Gated ◽

Cell Functions ◽

Erk Mapk ◽

Calmodulin Kinase

AbstractRas-Erk MAPK signaling controls many of the principal pathways involved in metazoan cell motility, drives metastasis of multiple cancer types and is targeted in chemotherapy. Yet, its putative roles in immune cell functions or in infections have remained elusive. Here, using primary dendritic cells (DCs) in an infection model with the protozoan Toxoplasma gondii, we show that two pathways activated by infection converge on Ras-Erk MAPK signaling to promote migration of parasitized DCs. We identify signaling through the receptor tyrosine kinase Met (also known as HGFR) as a driver of T. gondii-induced DC hypermotility. Further, we show that voltage-gated Ca2+channel (VGCC, subtype CaV1.3) signaling impacts the migratory activation of DCs via calmodulin-calmodulin kinase II. We report that VGCC and Met signaling converge on Ras GTPase to drive Erk1/2 phosphorylation and migratory activation of T. gondii-infected DCs. The data provide a molecular basis for the hypermigratory mesenchymal-to-amoeboid transition (MAT) of parasitized DCs. The emerging concept suggests that parasitized DCs acquire metastasis-like migratory properties to promote infection-related dissemination.

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The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells

Science Signaling ◽

10.1126/scisignal.aaz1053 ◽

2020 ◽

Vol 13 (634) ◽

pp. eaaz1053 ◽

Cited By ~ 3

Author(s):

Cesar A. Corzo ◽

Eugene Varfolomeev ◽

A. Francesca Setiadi ◽

Ross Francis ◽

Sha Klabunde ◽

...

Keyword(s):

Dendritic Cells ◽

B Cells ◽

Immune Complex ◽

Lupus Erythematosus ◽

Inflammatory Responses ◽

Interleukin 1 ◽

Disease Onset ◽

Human Memory ◽

Mapk Signaling ◽

Plasmacytoid Dendritic Cells

The dysregulation of multiple signaling pathways, including those through endosomal Toll-like receptors (TLRs), Fc gamma receptors (FcγR), and antigen receptors in B cells (BCR), promote an autoinflammatory loop in systemic lupus erythematosus (SLE). Here, we used selective small-molecule inhibitors to assess the regulatory roles of interleukin-1 receptor (IL-1R)–associated kinase 4 (IRAK4) and Bruton’s tyrosine kinase (BTK) in these pathways. The inhibition of IRAK4 repressed SLE immune complex– and TLR7-mediated activation of human plasmacytoid dendritic cells (pDCs). Correspondingly, the expression of interferon (IFN)–responsive genes (IRGs) in cells and in mice was positively regulated by the kinase activity of IRAK4. Both IRAK4 and BTK inhibition reduced the TLR7-mediated differentiation of human memory B cells into plasmablasts. TLR7-dependent inflammatory responses were differentially regulated by IRAK4 and BTK by cell type: In pDCs, IRAK4 positively regulated NF-κB and MAPK signaling, whereas in B cells, NF-κB and MAPK pathways were regulated by both BTK and IRAK4. In the pristane-induced lupus mouse model, inhibition of IRAK4 reduced the expression of IRGs during disease onset. Mice engineered to express kinase-deficient IRAK4 were protected from both chemical (pristane-induced) and genetic (NZB/W_F1 hybrid) models of lupus development. Our findings suggest that kinase inhibitors of IRAK4 might be a therapeutic in patients with SLE.

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miR-181a Modulation of ERK-MAPK Signaling Sustains DC-SIGN Expression and Limits Activation of Monocyte-Derived Dendritic Cells

Cell Reports ◽

10.1016/j.celrep.2020.02.077 ◽

2020 ◽

Vol 30 (11) ◽

pp. 3793-3805.e5

Author(s):

Clarice X. Lim ◽

Bernett Lee ◽

Olivia Geiger ◽

Christina Passegger ◽

Michaela Beitzinger ◽

...

Keyword(s):

Dendritic Cells ◽

Mapk Signaling ◽

Erk Mapk

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NFκB- and MAP-Kinase Signaling Contribute to the Activation of Murine Myeloid Dendritic Cells by a Flagellin A:Allergen Fusion Protein

Cells ◽

10.3390/cells8040355 ◽

2019 ◽

Vol 8 (4) ◽

pp. 355 ◽

Cited By ~ 1

Author(s):

Moeller ◽

Wolfheimer ◽

Goretzki ◽

Scheurer ◽

Schülke

Keyword(s):

Dendritic Cells ◽

Fusion Protein ◽

Map Kinase ◽

Inflammatory Cytokine ◽

Allergic Sensitization ◽

Birch Pollen ◽

Mapk Signaling ◽

Cytokine Secretion ◽

Myeloid Dendritic Cells ◽

Anti Inflammatory

Fusion proteins incorporating the TLR5-ligand flagellin are currently undergoing clinical trials as vaccine candidates for many diseases. We recently reported a flagellin:allergen fusion protein containing the TLR5-ligand flagellin A (FlaA) from Listeria monocytogenes and the major birch pollen allergen Bet v 1 (rFlaA:Betv1) to prevent allergic sensitization in an experimental mouse model. This study analyzes the signaling pathways contributing to rFlaA:Betv1-mediated pro- and anti-inflammatory cytokine secretion and cell metabolism in myeloid dendritic cells (mDCs) in vitro. The influence of mammalian target of rapamycin (mTOR)-, NF?B-, and MAP kinase (MAPK)-signaling on cytokine secretion and metabolic activity of bone marrow (BM)-derived mDCs stimulated with rFlaA:Betv1 were investigated by pre-treatment with either mTOR- (rapamycin), NF?B- (dexamethason, BMS-345541, TPCA-1, triptolide, or BAY-11) or MAPK- (SP600125, U0126, or SB202190) inhibitors, respectively. rFlaA:Betv1-mediated IL-10 secretion as well as activation of mDC metabolism, rather than pro-inflammatory cytokine secretion, were inhibited by rapamycin. Inhibition of NFκB-signaling suppressed rFlaA:Betv1-induced IL-12, while inhibition of MAPK-signaling dose-dependently suppressed rFlaA:Betv1-induced IL-10 as well as pro-inflammatory IL-6 and TNF-α production. Notably, with the exception of a partial JNK-dependency, rFlaA:Betv1-mediated effects on mDC metabolism were mostly NF?B- and MAPK-independent. Therefore, MAPK-mediated activation of both NFκB- and mTOR-signaling likely is a key pathway for the production of pro- and anti-inflammatory cytokines by flagellin fusion protein vaccines.

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Activation of Dendritic Cells by Ambient or Diesel-Particulate Matter Reveals Differential Toll-Like Receptor and p38 or ERKI/II MAPK Signaling.

10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a6082 ◽

2009 ◽

Author(s):

SJ Killedar ◽

SM Bauer ◽

SN Georas ◽

MA Williams

Keyword(s):

Dendritic Cells ◽

Particulate Matter ◽

Mapk Signaling ◽

Diesel Particulate Matter ◽

Toll Like Receptor ◽

Diesel Particulate

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Dendritic cells change IL-27 production pattern during childhood

BMC Research Notes ◽

10.1186/s13104-015-1182-0 ◽

2015 ◽

Vol 8 (1) ◽

Cited By ~ 5

Author(s):

Claudius U Meyer ◽

Julia Birkholz ◽

Nadine Weins ◽

Aysefa Doganci ◽

Stephan Gehring ◽

...

Keyword(s):

Dendritic Cells ◽

Production Pattern

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Extracellular signal–regulated protein kinase signaling pathway negatively regulates the phenotypic and functional maturation of monocyte-derived human dendritic cells

Blood ◽

10.1182/blood.v98.7.2175 ◽

2001 ◽

Vol 98 (7) ◽

pp. 2175-2182 ◽

Cited By ~ 156

Author(s):

Amaya Puig-Kröger ◽

Miguel Relloso ◽

Oskar Fernández-Capetillo ◽

Ana Zubiaga ◽

Augusto Silva ◽

...

Keyword(s):

Dendritic Cells ◽

Protein Kinase ◽

Intracellular Signaling ◽

Mannose Receptor ◽

Mapk Signaling ◽

Mitogen Activated Protein Kinase ◽

Functional Maturation ◽

Extracellular Signal ◽

Tnf Α ◽

Mitogen Activated Protein

Dendritic cells (DC) are highly specialized antigen-presenting cells that on activation by inflammatory stimuli (eg, tumor necrosis factor α [TNF-α] and interleukin-1β [IL-1β]) or infectious agents (eg, lipopolysaccharide [LPS]), mature and migrate into lymphoid organs. During maturation, DC acquire the capacity to prime and polarize resting naive T lymphocytes. Maturation of monocyte-derived DC (MDDC) is inhibited by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. This study found that in the presence of the mitogen-activated protein kinase kinase 1–extracellular signal-regulated kinase (ERK) inhibitors PD98059 or U0126, TNF-α– and LPS-induced phenotypic and functional maturation is enhanced. ERK pathway inhibitors increased expression of major histocompatibility complex and costimulatory molecules; loss of mannose-receptor–mediated endocytic activity; nuclear factor-κB DNA-binding activity; release of IL-12 p40; and allogeneic T-cell proliferation induced by LPS or TNF-α. Moreover, PD98059 and U0126 enhanced LPS-triggered production of IL-12 p70. In agreement with the effect of ERK inhibitors, maturation of MDDC was delayed in the presence of serum, an effect that was reversed by U0126. These results indicate that the ERK and p38 MAPK signaling pathways differentially regulate maturation of MDDC and suggest that their relative levels of activation might modulate the initial commitment of naive T-helper (Th) cells toward Th1 or Th2 subsets. The findings also suggest that maturation of MDDC might be pharmacologically modified by altering the relative levels of activation of both intracellular signaling routes.

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Tumor evasion of the immune system: inhibiting p38 MAPK signaling restores the function of dendritic cells in multiple myeloma

Blood ◽

10.1182/blood-2005-06-2486 ◽

2006 ◽

Vol 107 (6) ◽

pp. 2432-2439 ◽

Cited By ~ 68

Author(s):

Siqing Wang ◽

Jing Yang ◽

Jianfei Qian ◽

Michele Wezeman ◽

Larry W. Kwak ◽

...

Keyword(s):

Dendritic Cells ◽

P38 Mapk ◽

Neutralizing Antibodies ◽

Molecular Mechanisms ◽

Mapk Signaling ◽

Janus Kinase ◽

Mitogen Activated Protein Kinase ◽

Patients With Cancer ◽

And Function

AbstractDendritic cells (DCs) from patients with cancer are functionally defective, but the molecular mechanisms underlying these defects are poorly understood. In this study, we used the murine 5TGM1 myeloma model to examine the effects and mechanisms of tumor-derived factors on the differentiation and function of DCs. Myeloma cells or tumor culture conditioning medium (TCCM) were shown to inhibit the differentiation and function of BM-derived DCs (BMDCs), as evidenced by the down-regulated expression of DC-related surface molecules, decreased IL-12, and compromised capacity of the cells to activate allospecific T cells. Moreover, TCCM-treated BMDCs were inferior to normal BMDCs at priming tumor-specific immune responses in vivo. Neutralizing antibodies against IL-6, IL-10, and TGF-β partially abrogated the effects. TCCM treatment activated p38 mitogen-activated protein kinase (MAPK) and Janus kinase (JNK) but inhibited extracellular regulated kinase (ERK). Inhibiting p38 MAPK restored the phenotype, cytokine secretion, and function of TCCM-treated BMDCs. BMDCs from cultures with TCCM and p38 inhibitor was as efficacious as normal BMDCs at inducing tumor-specific antibody, type 1 T cell, and cytotoxic T lymphocyte (CTL) responses and at prolonging mouse survival. Thus, our results suggested that tumor-induced p38 MAPK activation and ERK inhibition in DCs may be a new mechanism for tumor evasion and that regulating these pathways during DC differentiation provides new strategies for generating potent DC vaccines for immunotherapy in patients with cancer. (Blood. 2006;107:2432-2439)

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