Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells

Kado, Sarah Y.; Chang, W. L. William; Nguyen, Aimy; Wolny, Monika; Shepherd, David M.; Vogel, Christoph F.A.

doi:10.1007/s00204-016-1880-y

Cited by 50 publications

(52 citation statements)

References 54 publications

(82 reference statements)

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“…Although we observed that AhR activation in keratinocytes by S. epidermidis did not directly influence NF-κB activation, we found that activation of both transcription factors, NF-κB and AhR, were crucial for the S. epidermidis-mediated induction of IL-1β in keratinocytes. This is in concordance with the necessity of NF-κB and AhR for IL-1β expression in TLR-and M. tuberculosis-activated dendritic cells and macrophages [40,41].…”

Section: Discussionsupporting

confidence: 87%

Staphylococcus epidermidis Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

Rademacher¹,

Simanski²,

Hesse³

et al. 2018

J Innate Immun

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Bacterial challenge of keratinocytes with the abundant skin commensal Staphylococcus epidermidis induces distinct innate immune responses, but the underlying molecular mechanisms are still emerging. We report that the aryl hydrocarbon receptor (AhR) was activated in human primary keratinocytes infected with S. epidermidis, leading to induction of the AhR-responsive gene cytochrome P450 1A1 (CYP1A1). In addition, functional AhR was required for S. epidermidis-mediated induction of IL-1β expression in keratinocytes. AhR-dependent gene induction of IL-1β and CYP1A1 was mediated by factor(s) < 2 kDa secreted by S. epidermidis. Blockade of the AhR in a 3D organotypic skin equivalent infected with S. epidermidis attenuated the S. epidermidis-induced CYP1A1 and IL-1β expression. Moreover, S. epidermidis also induced expression of IL-1α and of the antimicrobial peptide human β-defensin-3 in an AhR-dependent manner in a 3D skin equivalent. An increased outgrowth of S. epidermidis on the surface of skin explants treated with a specific AhR inhibitor further indicate a pivotal role of the AhR in mediating an epidermal defense response. Taken together, our data expand the role of the AhR in innate immunity and support a previously unappreciated contribution for the AhR in cutaneous defense.

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Section: Discussionsupporting

confidence: 87%

Staphylococcus epidermidis Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

Rademacher¹,

Simanski²,

Hesse³

et al. 2018

J Innate Immun

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“…To the contrary, our data showed that LPS could not induce Ahr expression (data not shown) and that AHR-dependent Cyp1a1 induction was inhibited in these cells. However, similar to what has been reported in moDCs [45], we also observed that AHR antagonized some proinflammatory cytokines (e.g., IL-6, CCL3) but enhanced the production of others (e.g., IL-8). Likewise, AHR activation increased the expression of IL-23 in M-CSFderived macrophages [55].…”

Section: Discussionsupporting

confidence: 91%

“…6C). In human moDCs, AHR has been reported to enhance the production of IL-1b and IL-8 [45], contrary to its inhibitory effect on other proinflammatory cytokines [34]. Although we were unable to detect significant production of IL-1b in GM-MDMs (data not shown), we too found that AHR activation by FICZ significantly enhanced the production of IL-8 in GM-MDMs stimulated with LPS ( Fig.…”

Section: Ahr Activation Regulates the Proinflammatory Cytokine Responmentioning

confidence: 54%

Suppression of CYP1 members of the AHR response by pathogen-associated molecular patterns

Peres

Zamboni

King

et al. 2017

Journal of Leukocyte Biology

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that triggers a broad response, which includes the regulation of proinflammatory cytokine production by monocytes and macrophages. AHR is negatively regulated by a set of genes that it transcriptionally activates, including the AHR repressor () and the cytochrome P450 1 () family, which are critical for preventing exacerbated AHR activity. An imbalance in these regulatory mechanisms has been shown to cause severe defects in lymphoid cells. Therefore, we wanted to assess how AHR activation is regulated in monocytes and macrophages in the context of innate immune responses induced by pathogen-associated molecular patterns (PAMPs). We found that concomitant stimulation of primary human monocytes with PAMPs and the AHR agonist 6-formylindolo(3,2-b)carbazole (FICZ) led to a selective dose-dependent inhibition of family members induction. Two other AHR-dependent genes [ and NADPH quinone dehydrogenase 1 ()] were not affected under these conditions, suggesting a split in the AHR regulation by PAMPs. This down-regulation of family members did not require de novo protein production nor signaling through p38, ERK, or PI3K-Akt-mammalian target of rapamycin (mTOR) pathways. Furthermore, such a split regulation of the AHR response was more apparent in GM-CSF-derived macrophages, a finding corroborated at the functional level by decreased CYP1 activity and decreased proinflammatory cytokine production in response to FICZ and LPS. Collectively, our findings identify a role for pattern recognition receptor (PRR) signaling in regulating the AHR response through selective down-regulation of expression in human monocytes and macrophages.

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“…Indeed, AhR plays an important role in the human immune system [9] and its interaction with the TLR/NF-κB signaling pathway has recently been elucidated [11-13]. The presence of bacterial originating TLR2 ligands seems to be crucial for detoxification of luminal carcinogens by CYP1A1 in the intestine and indicates a complex interplay between the immune system of the host and intestinal bacteria with detoxification mechanisms [23].…”

Section: Discussionmentioning

confidence: 99%

“…2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) is a high-affinity AhR ligand that is frequently used to investigate biological processes impacted by AhR activation [10]. In addition, close interactions between TLRs, NF-κB, and the AhR signaling pathway have been studied in human dendritic cells [11] and macrophages [12, 13], which contribute to immune dysfunction, metabolism of xenobiotics, and carcinogenesis [14]. …”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor Modulates the Expression of TNF-α and IL-8 in Human Sebocytes via the MyD88-p65NF-κB/p38MAPK Signaling Pathways

et al. 2018

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Activation of Toll-like receptor (TLR)-2 and subsequent inflammatory response contribute to lesion development in acne vulgaris. A cross-talk between aryl hydrocarbon receptor (AhR), a cytosolic receptor protein that responds to environmental and physiological stress, and TLRs has recently been reported. In this study, we explored the possible role of AhR in the effects induced on cultured human SZ95 sebocytes by peptidoglycan (PGN), a classic TLR2 agonist. PGN-induced secretion of inflammatory factors TNF-α and IL-8 in human SZ95 sebocytes was suppressed after knockdown of AhR and pretreatment with the AhR antagonist CH223191. In addition, the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) enhanced TNF-α and IL-8 secretion in PGN-pretreated sebocytes. Furthermore, PGN-induced expression of myeloid differentiation factor 88 (MyD88), phospho-p38MAPK (p-p38MAPK), and p-p65NF-κB was strengthened by TCDD and repressed by CH223191. AhR inhibition by transfecting shRNA blocked the ability of PGN to stimulate phosphorylation of p38MAPK and p65NF-κB in SZ95 sebocytes. Overall, these data demonstrate that AhR is able to modulate PGN-induced expression of TNF-α and IL-8 in human SZ95 sebocytes involving the MyD88-p65NF-κB/p38MAPK signaling pathway, which probably indicates a new mechanism in TLR2-mediated acne.

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Aryl hydrocarbon receptor signaling modifies Toll-like receptor-regulated responses in human dendritic cells

Cited by 50 publications

References 54 publications

<b><i>Staphylococcus epidermidis</i></b> Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

<b><i>Staphylococcus epidermidis</i></b> Activates Aryl Hydrocarbon Receptor Signaling in Human Keratinocytes: Implications for Cutaneous Defense

Suppression of CYP1 members of the AHR response by pathogen-associated molecular patterns

Aryl Hydrocarbon Receptor Modulates the Expression of TNF-α and IL-8 in Human Sebocytes via the MyD88-p65NF-κB/p38MAPK Signaling Pathways

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