Impact of p38 mitogen-activated protein kinase inhibition on immunostimulatory properties of human 6-sulfo LacNAc dendritic cells

Langosch, Saskia; Wehner, Rebekka; Malecka, Ania; Franks, Hester; Schäkel, Knut; Bachmann, Michael; Jackson, Andrew M.; Schmitz, Marc

doi:10.1016/j.imbio.2015.09.012

Cited by 6 publications

(5 citation statements)

References 86 publications

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“…To elucidate the mechanism by which C5a downmodulates DC pro-inflammatory cytokine production, potential crosstalk was investigated between known C5aR and TLR signaling cascades involving the phosphorylation of ERK1/2, p38, or JNK or the activation of NF-κB (1, 9, 27–29). Since slanDCs comprise 0.5–2% of the PBMC fraction on average, only low numbers of slanDC could be obtained from each donor (ranging from 0.8 to 3.0 × 10 6 slanDC per buffy coat).…”

Section: Resultsmentioning

confidence: 99%

Anaphylatoxin C5a Regulates 6-Sulfo-LacNAc Dendritic Cell Function in Human through Crosstalk with Toll-Like Receptor-Induced CREB Signaling

et al. 2017

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Activation of antigen-presenting dendritic cells (DCs) and the complement system are essential early events in the immune defense against invading pathogens. Recently, we and others demonstrated immunological crosstalk between signaling from receptors recognizing complement activation products and PAMPs on DCs. This affects DC effector function, as demonstrated by the finding that C5a prevents induction of pro-inflammatory cytokines by toll-like receptor (TLR) ligands in human monocyte-derived DCs (moDCs). Here, we demonstrate that this regulatory crosstalk is specifically important in 6-sulfo LacNAc dendritic cells (slanDCs), the most pro-inflammatory DC subset found in human. C5aR and TLR signaling show profound interference in the ERK/p38/CREB1 signaling pathways. C5aR signaling accelerates TLR-induced CREB1 phosphorylation both in moDC and slanDC. This is key in the regulatory effect of C5a on pro-inflammatory DC maturation by mediating induction of IL-10, which subsequently inhibits pro-inflammatory cytokine production via negative feedback signaling. Importantly, the regulatory effect of C5a affects T-cell immunity by decreasing Th1 and cytotoxic CD8 T-cell responses. The finding that the pro-inflammatory effector function of slanDC can be down modulated by activation products of the complement system highlights the existence of intricate regulatory interactions between various arms of the immune system. Intensive immune monitoring of patients suffering from complement-mediated diseases or patients receiving complement modulating compounds can give more inside in the contribution of complement receptor and TLR crosstalk in APCs in disease.

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Section: Resultsmentioning

confidence: 99%

Anaphylatoxin C5a Regulates 6-Sulfo-LacNAc Dendritic Cell Function in Human through Crosstalk with Toll-Like Receptor-Induced CREB Signaling

et al. 2017

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“…It has been recently shown that the IL-12 secreting capacity of Slan-DCs can be inhibited by mesenchymal stem cells through the secretion of prostaglandin E 2 via a p38 mitogen-activated protein kinase inhibition. 24 Thus, it is possible that this pathway is involved in IL-12 inhibition by MM cells.…”

Section: Discussionmentioning

confidence: 99%

Quantitative and functional alterations of 6-sulfo LacNac dendritic cells in multiple myeloma

et al. 2018

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Multiple myeloma (MM) results from expansion of abnormal plasma cells in the bone marrow (BM). Previous studies have shown that monocytes play a crucial role in MM pathophysiology. A 6-sulfo LacNAc-expressing population of dendritic cells (Slan-DCs) that overlaps with intermediate and non-classical monocytes in terms of phenotype has been described. Slan-DCs represent a circulating and tissue proinflammatory myeloid population which has been shown to play a role in different cancer contexts, and which exhibits a remarkable plasticity. Herein, we studied Slan-DCs from the BM and blood of MM patients. We performed quantitative and functional analyses of these cells from 54 patients with newly diagnosed, symptomatic MM, 21 patients with MGUS and 24 responding MM patients. We found that circulating Slan-DCs were significantly decreased in MM patients as compared to those of healthy donors or patients with MGUS, while CD14+CD16+ intermediate monocytes accumulate in the BM. Moreover, after activation with TLR7/8 ligand R848, IL-12-producing Slan-DCs from the BM or peripheral blood from MM patients were decreased as compared with healthy donors. We show that MM cell lines or MM cells isolated from patients at diagnosis were able to inhibit the production of IL-12 by Slan-DCs, as well as to shift the phenotype of Slan-DCs towards an intermediate monocyte-like phenotype. Finally, Slan-DCs that have been cultured with MM cells reduced their capacity to induce T cell proliferation and Th1 polarization. We conclude that Slan-DCs represent previously unrecognized players in MM development and may represent a therapeutic target.

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“…Previously we established that the p38 MAPK pathway serves a special function in cDC2 cells where p38i increases IL-12 expression, whereas p38i inhibits IL-12 in moDC and slanDC. 25,33 We therefore hypothesized that inhibition of p38 MAPK in cDC2 would reverse the immunosuppressive effects of Dex and TL and initially characterized the impact of selective p38 MAPK inhibitors on the p38-MK2 pathway. Activation with Poly I:C/R848 increased phosphorylation of p38 MAPK and its downstream target, MK2, by 30 min (Figure 5(a)).…”

Section: Inhibition Of P38 Mapk Reverses Dex and Tl Induced Dysfunctimentioning

confidence: 99%

Impaired circulating myeloid CD1c+ dendritic cell function in human glioblastoma is restored by p38 inhibition – implications for the next generation of DC vaccines

Adhikaree¹,

Franks²,

Televantos³

et al. 2019

OncoImmunology

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2019) Impaired circulating myeloid CD1c+ dendritic cell function in human glioblastoma is restored by p38 inhibition -implications for the next generation of DC vaccines, OncoImmunology, 8:7, e1593803, ABSTRACT Current treatments for glioblastoma (GBM) have limited efficacy and significant morbidity and therefore new strategies are urgently needed. Dendritic cells have the power to create anti-tumor immune responses. The greater potency of circulating dendritic cells (DC) over laboratory-generated monocytederived DC makes them exciting new immunotherapeutic candidates. To determine the immune status of GBM patients we initially investigated the frequency and function of circulating DC subsets. Furthermore, we tested the therapeutic potential of inhibiting the p38 mitogen-activated protein kinase pathway (p38i) in circulating DC to overcome DC dysfunction.GBM patients (n = 16) had significantly reduced numbers of the major myeloid circulating dendritic cell (cDC2) and plasmacytoid DC vs healthy controls; 1736 vs 4975 (p = 0.028) and 893 vs 2287 cells/mL (P = <0.001) respectively. This inversely correlated with dexamethasone (Dex) dose in a log-linear model, and disease status. Patients' cDC2 were immature with impaired interleukin (IL)-12 secretion, reduced IL-12:IL-10 ratio, and low HLA-DR and CD86 expression. Exposure of healthy donor cDC2 to Dex or GBM cell lysate resulted in a similar low IL-12:IL-10 ratio. Inhibition of p38 restored the IL-12:IL-10 balance in Dex or tumor lysate-conditioned healthy cDC2 and enhanced T-cell proliferation and interferon-gamma (IFNγ) production. Importantly, patient-derived cDC2 showed a similar reversal of DC dysfunction with p38i. This study demonstrates the therapeutic potential of developing the next generation of DC vaccines using enhanced p38i-conditioned cDC2. We will therefore shortly embark on a clinical trial of adoptively transferred, p38 MAPKinhibited cDC2 in adults with GBM. ARTICLE HISTORY

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Impact of p38 mitogen-activated protein kinase inhibition on immunostimulatory properties of human 6-sulfo LacNAc dendritic cells

Cited by 6 publications

References 86 publications

Anaphylatoxin C5a Regulates 6-Sulfo-LacNAc Dendritic Cell Function in Human through Crosstalk with Toll-Like Receptor-Induced CREB Signaling

Anaphylatoxin C5a Regulates 6-Sulfo-LacNAc Dendritic Cell Function in Human through Crosstalk with Toll-Like Receptor-Induced CREB Signaling

Quantitative and functional alterations of 6-sulfo LacNac dendritic cells in multiple myeloma

Impaired circulating myeloid CD1c+ dendritic cell function in human glioblastoma is restored by p38 inhibition – implications for the next generation of DC vaccines

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