Hypoxia and TLR9 activation drive CXCL4 production in systemic sclerosis plasmacytoid dendritic cells via mtROS and HIF-2α

Rheumatology ◽  
2021 ◽  
Author(s):  
Andrea Ottria ◽  
Maili Zimmermann ◽  
Laurent M Paardekooper ◽  
Tiago Carvalheiro ◽  
Nadia Vazirpanah ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Systemic Sclerosis ◽  
Complex Disease ◽  
Inflammatory Diseases ◽  
Atmospheric Oxygen ◽  
Predictive Biomarker ◽  
Plasmacytoid Dendritic Cells ◽  
Vascular Abnormalities ◽  
Tlr Agonists ◽  
Gene And Protein Expression

Abstract Objective Systemic sclerosis (SSc) is a complex disease characterized by vascular abnormalities and inflammation culminating in hypoxia and excessive fibrosis. Previously, we identified CXCL4 as a novel predictive biomarker in SSc. Although CXCL4 is well-studied, the mechanisms driving its production are unclear. The aim of this study was to elucidate the mechanisms leading to CXCL4 production. Methods Plasmacytoid dendritic cells (pDCs) from 97 healthy controls and 70 SSc patients were cultured in the presence of hypoxia or atmospheric oxygen level and/or stimulated with several TLR-agonists. Further, pro-inflammatory cytokine production, CXCL4, HIF-1α and HIF-2α gene and protein expression were assessed using ELISA, Luminex, qPCR, FACS and western blot assays. Results CXCL4 release was potentiated only when pDCs were simultaneously exposed to hypoxia and TLR9 agonist (p < 0.0001). Here, we demonstrated that CXCL4 production is dependent on the overproduction of mitochondrial reactive oxygen species (mtROS) (p = 0.0079) leading to stabilization of HIF-2α (p = 0.029). In addition, we show that hypoxia is fundamental for CXCL4 production by umbilical cord (uc)CD34 derived pDCs. Conclusion TLR-mediated activation of immune cells in the presence of hypoxia underpins the pathogenic production of CXCL4 in SSc. Blocking either mtROS or HIF-2α pathways may therapeutically attenuate the contribution of CXCL4 to SSc and other inflammatory diseases driven by CXCL4.

Abstract 107: Depletion of Plasmacytoid Dendritic Cells Inhibits Experimental Abdominal Aortic Aneurysms

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Baohui Xu ◽  
Haojun Xuan ◽  
Naoki Fujimura ◽  
Sara A Michie ◽  
Ronald L Dalman
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Diseases ◽  
Myeloid Cells ◽  
Abdominal Aortic Aneurysms ◽  
Plasmacytoid Dendritic Cells ◽  
Aortic Aneurysms ◽  
Major Type ◽  
Abdominal Aortic

Introduction: Abdominal aortic aneurysms (AAA) manifest histologic features consistent with other chronic inflammatory diseases. Infiltrating mural myeloid cells (e.g. macrophages) are already recognized as important contributors to aneurysm pathogenesis, however, the role of plasmacytoid dendritic cells (pDC), major type 1 interferon-producing myeloid cells involving in autoimmune diseases and atherosclerosis, has not been previously investigated in this context. Methods and Results: AAAs were created in 12 week old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase (PPE). AAA development and progression were assessed via serial ultrasound determination of aortic diameter in vivo , and histology at sacrifice. The fraction of circulating leukocytes identified as pDCs was significantly increased immediately following PPE infusion (aneurysm initiation). Treatment with mPDCA-1 mAb (400 μg i.p. q.o.d.), beginning one day prior to PPE infusion, depleted more than 90% of bone marrow, spleen and peripheral blood pDCs (data not shown) and suppressed subsequent aneurysm development and progression compared to that noted in PPE-infused mice treated with control mAb. mPDCA-1 treatment promoted aortic medial elastin and smooth muscle preservation, while limiting mural macrophage accumulation and neocapillary formation. Conclusion: These findings suggest a role for plasmacytoid dendritic cells in promoting the initiation and progression of experimental abdominal aortic aneurysms.

scholarly journals Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8

2018 ◽  
Vol 10 (423) ◽  
pp. eaam8458 ◽  
Author(s):  
Marie Dominique Ah Kioon ◽  
Claudio Tripodo ◽  
David Fernandez ◽  
Kyriakos A. Kirou ◽  
Robert F. Spiera ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Systemic Sclerosis ◽  
Plasmacytoid Dendritic Cells

Low Blood Counts of Memory/Effector CD8 T Cells, Gamma/Delta T Cells, Memory B Cells and Plasmacytoid Dendritic Cells and High Counts of Th2 Cells in Systemic Sclerosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4917-4917
Author(s):  
Jan Storek ◽  
Rob Woolson ◽  
Paul K. Wallace ◽  
Gregory Sempowski ◽  
Peter A. McSweeney ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Systemic Sclerosis ◽  
B Cells ◽  
Cd8 T Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Memory B Cells ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Memory Cd8 T Cells

Abstract Abstract 4917 Introduction: Systemic sclerosis (SSc) is presumed to result from aberrant activation of autoreactive T cells. However, the exact pathogenesis of SSc is not known. Patients and Methods: To contribute to the understanding of the immunopathology of systemic sclerosis (SSc), we compared blood counts of multiple lymphocyte subsets between 20 adult SSc patients not treated with immunomodulatory drugs and healthy controls. The patients had to fit entry criteria for SCOT trial (Scleroderma – Cyclophosphamide or Transplantation?, www.sclerodermatrial.org), i.e, 1. symptoms for no longer than 5 years (except for Raynaud's phenomenon), 2. diffuse scleroderma, and 3. either moderate lung involvement (forced vital capacity (FVC) or diffusion of carbon monoxide (DLCO) between 45 and 70% predicted) or moderate kidney involvement (history of hypertensive renal crisis, but normal renal function at study entry). Multiparameter flow cytometry was used for the determination of the lymphocyte subset counts. Results: Counts of the following subsets were significantly lower in the patients compared to the controls: total T cells (median 1316 vs 2088/ul, p=0.015), total CD8 T cells (273 vs 580/ul, p<0.001), central memory CD8 T cells (23 vs 87/ul, p<0.001), effector memory CD8 T cells (17 vs 39/ul, p=0.015), effector CD8 T cells (28 vs 68/ul, p=0.001), gamma/delta T cells (31 vs 77/ul, p<0.001), switched (IgM/DàIgG/A isotype switched) memory B cells (6 vs 26/ul, p<0.001), non-switched memory B cells (7 vs 17/ul, p=0.004), and plasmacytoid dendritic cells (2 vs 6/ul, p=0.002). Counts of Th2-biased (producing interleukin-4 upon polyclonal stimulation) CD4 as well as CD8 T cells were significantly higher in the patients compared to the controls (248 vs 139/ul for CD4, p=0.002, and 259 vs 164/ul for CD8, p<0.001). Conclusion: Immunopathology of SSc is complex. Low blood counts of memory/effector CD8 T cells, gamma/delta T cells, memory B cells and plasmacytoid dendritic cells and Th2-biased T cells may play a role in the pathogenesis of SSc. However, cause and effect relations need to be established. Given previous reports of increased numbers of CD8 and gamma/delta T cells in the affected tissues of patients with systemic sclerosis and increased numbers of plasmacytoid dendritic cells in the affected tissues of patients with autoimmune diseases (compared to healthy individuals) (Prescott RJ et al: J Pathol 166 (1992) 255–63, Atamas SP et al: Arthritis Rheum 42 (1999) 1168–78, Giacomelli R et al: Arthritis Rheum 41 (1998) 327–34, Yurovski VV et al: J Immunol 153 (1994) 881–91, Nestle FO et al: J Exp Med 202 (2005) 35–43, Farkas L et al: Am J Pathol 159 (2001) 237–43), it is possible that the low blood counts of CD8 T cells, gamma/delta T cells and plasmacytoid dendritic cells result from redistribution of these cells from blood to affected tissues. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expression of TIM-3 on Plasmacytoid Dendritic Cells as a Predictive Biomarker of Decline in HIV-1 RNA Level during ART

Viruses ◽  
2018 ◽  
Vol 10 (4) ◽  
pp. 154 ◽  
Author(s):  
Albert Font-Haro ◽  
Vaclav Janovec ◽  
Tomas Hofman ◽  
Ladislav Machala ◽  
David Jilich ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Predictive Biomarker ◽  
Plasmacytoid Dendritic Cells ◽  
Hiv 1

scholarly journals Virus or TLR Agonists Induce TRAIL-Mediated Cytotoxic Activity of Plasmacytoid Dendritic Cells

2005 ◽  
Vol 176 (1) ◽  
pp. 248-255 ◽  
Author(s):  
Laurence Chaperot ◽  
Ariane Blum ◽  
Olivier Manches ◽  
Gabrielle Lui ◽  
Juliette Angel ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cytotoxic Activity ◽  
Plasmacytoid Dendritic Cells ◽  
Tlr Agonists

Association of MicroRNA-618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis

2017 ◽  
Vol 69 (9) ◽  
pp. 1891-1902 ◽  
Author(s):  
Marzia Rossato ◽  
Alsya J. Affandi ◽  
Soley Thordardottir ◽  
Catharina G. K. Wichers ◽  
Marta Cossu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Systemic Sclerosis ◽  
Plasmacytoid Dendritic Cells

scholarly journals Targeting human plasmacytoid dendritic cells through BDCA2 prevents skin inflammation and fibrosis in a novel xenotransplant mouse model of scleroderma

2021 ◽  
pp. annrheumdis-2020-218439
Author(s):  
Rebecca L Ross ◽  
Clarissa Corinaldesi ◽  
Gemma Migneco ◽  
Ian M Carr ◽  
Agne Antanaviciute ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Ex Vivo ◽  
Severe Combined Immunodeficiency ◽  
Indirect Evidence ◽  
Plasmacytoid Dendritic Cells ◽  
Induced Response ◽  
Type I ◽  
Therapeutic Application ◽  
Gene And Protein Expression

ObjectivesPlasmacytoid dendritic cells (pDC) have been implicated in the pathogenesis of autoimmune diseases, such as scleroderma (SSc). However, this has been derived from indirect evidence using ex vivo human samples or mouse pDC in vivo. We have developed human-specific pDC models to directly identify their role in inflammation and fibrosis, as well as attenuation of pDC function with BDCA2-targeting to determine its therapeutic application.MethodsRNAseq of human pDC with TLR9 agonist ODN2216 and humanised monoclonal BDCA2 antibody, CBS004. Organotypic skin rafts consisting of fibroblasts and keratinocytes were stimulated with supernatant from TLR9-stimulated pDC and with CBS004. Human pDC were xenotransplanted into Nonobese diabetic/severe combined immunodeficiency (NOD SCID) mice treated with Aldara (inflammatory model), or bleomycin (fibrotic model) with CBS004 or human IgG control. Skin punch biopsies were used to assess gene and protein expression.ResultsRNAseq shows TLR9-induced activation of human pDC goes beyond type I interferon (IFN) secretion, which is functionally inactivated by BDCA2-targeting. Consistent with these findings, we show that BDCA2-targeting of pDC can completely suppress in vitro skin IFN-induced response. Most importantly, xenotransplantation of human pDC significantly increased in vivo skin IFN-induced response to TLR agonist and strongly enhanced fibrotic and immune response to bleomycin compared with controls. In these contexts, BDCA2-targeting suppressed human pDC-specific pathological responses.ConclusionsOur data indicate that human pDC play a key role in inflammation and immune-driven skin fibrosis, which can be effectively blocked by BDCA2-targeting, providing direct evidence supporting the development of attenuation of pDC function as a therapeutic application for SSc.

scholarly journals Toll-Like Receptor 7 (TLR-7) and TLR-9 Agonists Improve Hepatitis C Virus Replication and Infectivity Inhibition by Plasmacytoid Dendritic Cells

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
B. Dominguez-Molina ◽  
K. Machmach ◽  
C. Perales ◽  
L. Tarancon-Diez ◽  
I. Gallego ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Activity ◽  
Immune Cells ◽  
Plasmacytoid Dendritic Cells ◽  
Hepatoma Cell Line ◽  
Toll Like Receptor ◽  
Tlr Agonists ◽  
Coculture System

ABSTRACT Plasmacytoid dendritic cells (pDCs) are innate immune cells with high antiviral activity triggered by Toll-like receptor 7 (TLR-7) and TLR-9 stimulation. Moreover, they are important mediators between innate and adaptive immunity. Although nowadays there is available an effective therapeutic arsenal against hepatitis C virus (HCV), a protective vaccine is not available. We have analyzed the pDCs’ response to HCV infection in a hepatitis C virus (HCV)-Huh7.5 virus-cell system, which allows completion of the virus infectious cycle. pDCs were cocultured following human immunodeficiency virus (HIV) aldrithiol-2 (AT-2 [TLR-7 agonist]) inactivation and CpG (TLR-9 agonist) stimulation. We employed three virus derivatives—wild-type Jc1, interferon (IFN)-resistant virus IR, and high-replicative-fitness virus P100—in order to explore additional IFN-α-related virus inhibition mechanisms. pDCs inhibited HCV infectivity and replication and produced IFN-α. After TLR-7 and TLR-9 stimulation, inhibition of infectivity and IFN-α production by pDCs were enhanced. TLR-7 stimulation drove higher TNF-related apoptosis-inducing ligand (TRAIL) expression in pDCs. Additionally, TLR-7- and TLR-9-stimulated pDCs exhibited a mature phenotype, improving the antigen presentation and lymph node homing-related markers. In conclusion, pDCs could serve as a drug target against HCV in order to improve antiviral activity and as an enhancer of viral immunization. IMPORTANCE We implemented a coculture system of pDCs with HCV-infected hepatoma cell line, Huh7.5. We used three HCV derivatives in order to gain insight into pDCs’ behavior against HCV and associated antiviral mechanisms. The results with this cell coculture system support the capacity of pDCs to inhibit HCV replication and infectivity mainly via IFN-α, but also through additional mechanisms associated with pDC maturation. We provided evidence that TLR agonists can enhance antiviral pDCs’ function and can induce phenotypic changes that may facilitate the interplay with other immune cells. These findings suggest the possibility of including TLR agonists in the strategies of HCV vaccine development.

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