Faculty Opinions recommendation of CTLA-4-mediated transendocytosis of costimulatory molecules primarily targets migratory dendritic cells.

Aims. The aim of this study was to evaluate the protective effects of Er Miao San (EMS) and the regulative function of bone marrow-derived dendritic cells (BMDCs) on adjuvant arthritis (AA) in rats. Methods. The ethyl acetate part of EMS (3 g/kg, 1.5 g/kg, and 0.75 g/kg) was orally administered from day 15 after immunization to day 29. The polyarthritis index and paw swelling were measured, the ankle joint pathological changes were observed using hematoxylin-eosin (HE) staining, and the spleen and thymus index were determined. Moreover, T and B cell proliferation were determined using the CCK-8 assay. The expression of BMDC surface costimulatory molecules and inflammatory factors were determined using flow cytometry and ELISA kits, respectively. Results. Compared with the AA model rats, the ethyl acetate fraction of EMS obviously reduced paw swelling (from 1.0 to 0.7) and the polyarthritis index (from 12 to 9) P < 0.01 and improved the severity of histopathology P < 0.01 . The treatment using ethyl acetate fraction of EMS significantly reduced the spleen and thymus index P < 0.01 and inhibited T and B cell proliferation P < 0.01 . Moreover, EMS significantly modulated the expression of surface costimulatory molecules in BMDCs, including CD40, CD80, CD86, and major histocompatibility complex class II (MHC-II) P < 0.01 . The results also showed that the ethyl acetate part of EMS significant inhibited the levels of proinflammatory cytokines interleukin- (IL-) 23 tumor necrosis factor- (TNF-) α and inflammatory factor prostaglandin (PG) E2 in the supernatant of BMDCs. However, the level of anti-inflammatory cytokine IL-10 was significantly increased P < 0.01 . Conclusion. These results suggest that the ethyl acetate part of EMS has better protective effects on AA rats, probably by regulating the function of BMDCs and modulating the balance of cytokines.

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Resiquimod-Mediated Activation of Plasmacytoid Dendritic Cells Is Amplified in Multiple Sclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms20112811 ◽

2019 ◽

Vol 20 (11) ◽

pp. 2811 ◽

Cited By ~ 2

Author(s):

Marta Corsetti ◽

Gabriella Ruocco ◽

Serena Ruggieri ◽

Claudio Gasperini ◽

Luca Battistini ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dendritic Cells ◽

Viral Infection ◽

Adaptive Immune Response ◽

Plasmacytoid Dendritic Cells ◽

Costimulatory Molecules ◽

Strong Impact ◽

Myeloid Dendritic Cells ◽

Healthy Donors ◽

Environmental Causes

Background: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system. The cause of multiple sclerosis is unknown but there are several evidences that associate the genetic basis of the disease with environmental causes. An important association between viral infection and development of MS is clearly demonstrated. Viruses have a strong impact on innate immune cells. In particular, myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs), are able to respond to viruses and to activate the adaptive immune response. Methods: In this study we mimic viral infection using synthetic single-strand RNA, Resiquimod, and we compared the response of both DC subsets derived from healthy donors and MS patients by characterizing the expression of costimulatory molecules on the DC surface. Results: We found that pDCs from MS patients express higher levels of OX40-L, HLA-DR, and CD86 than healthy donors. Moreover, we found that blood cells from MS patients and healthy donors upon Resiquimod-stimulation are enriched in a subpopulation of pDCs, characterized by a high amount of costimulatory molecules. Conclusion: Overall, these results indicate that activation of pDCs is enhanced in MS, likely due to a latent viral infection, and that costimulatory molecules expressed on pDCs could mediate a protective response against the viral trigger of autoimmunity.

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Role of the p38 MAPK/C/EBPβ Pathway in the Regulation of Phenotype and IL-10 and IL-12 Production by Tolerogenic Bone Marrow-Derived Dendritic Cells

Cells ◽

10.3390/cells7120256 ◽

2018 ◽

Vol 7 (12) ◽

pp. 256 ◽

Cited By ~ 8

Author(s):

Chantal Guindi ◽

Alexandre Cloutier ◽

Simon Gaudreau ◽

Echarki Zerif ◽

Patrick P. McDonald ◽

...

Keyword(s):

Bone Marrow ◽

Dendritic Cells ◽

Dna Binding ◽

P38 Mapk ◽

Costimulatory Molecules ◽

Binding Activity ◽

Gm Csf ◽

Dna Binding Activity ◽

Factor C

Dendritic cells (DCs) play a major role in innate and adaptive immunity and self-immune tolerance. Immunogenic versus tolerogenic DC functions are dictated by their levels of costimulatory molecules and their cytokine expression profile. The transcription factor C/EBPβ regulates the expression of several inflammatory genes in many cell types including macrophages. However, little is known regarding the role of C/EBPβ in tolerogenic versus immunogenic DCs functions. We have previously reported that bone marrow-derived DCs generated with GM-CSF (GM/DCs) acquire the signature of semi-mature tolerogenic IL-10-producing DCs as opposed to immunogenic DCs generated with GM-CSF and IL-4 (IL-4/DCs). Here, we show that tolerogenic GM/DCs exhibit higher levels of phosphorylation and enhanced DNA binding activity of C/EBPβ and CREB than immunogenic IL-4/DCs. We also show that the p38 MAPK/CREB axis and GSK3 play an important role in regulating C/EBPβ phosphorylation and DNA binding activity. Inhibition of p38 MAPK in GM/DCs resulted in a drastic decrease of C/EBPβ and CREB DNA binding activities, a reduction of their IL-10 production and an increase of their IL-12p70 production, a characteristic of immunogenic IL-4/DCs. We also present evidence that GSK3 inhibition in GM/DCs reduced C/EBPβ DNA binding activity and increased expression of costimulatory molecules in GM/DCs and their production of IL-10. Analysis of GM/DCs of C/EBPβ−/− mice showed that C/EBPβ was essential to maintain the semimature phenotype and the production of IL-10 as well as low CD4+ T cell proliferation. Our results highlight the importance of the p38MAPK-C/EBPβ pathway in regulating phenotype and function of tolerogenic GM/DCs.

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Tropomodulin1 Expression Increases Upon Maturation in Dendritic Cells and Promotes Their Maturation and Immune Functions

Frontiers in Immunology ◽

10.3389/fimmu.2020.587441 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xianmei Liu ◽

Xue Xia ◽

Xifu Wang ◽

Jing Zhou ◽

Lanping Amy Sung ◽

...

Keyword(s):

Dendritic Cells ◽

Actin Cytoskeleton ◽

Costimulatory Molecules ◽

Cell Stiffness ◽

Actin Binding ◽

Immune Functions ◽

Dc Functions ◽

Tlr4 Signaling ◽

Functional Changes ◽

Dc Maturation

Dendritic cells (DCs) are the most potent antigen-presenting cells. Upon maturation, DCs express costimulatory molecules and migrate to the lymph nodes to present antigens to T cells. The actin cytoskeleton plays key roles in multiple aspects of DC functions. However, little is known about the mechanisms and identities of actin-binding proteins that control DC maturation and maturation-associated functional changes. Tropomodulin1 (Tmod1), an actin-capping protein, controls actin depolymerization and nucleation. We found that Tmod1 was expressed in bone marrow-derived immature DCs and was significantly upregulated upon lipopolysaccharide (LPS)-induced DC maturation. By characterizing LPS-induced mature DCs (mDCs) from Tmod1 knockout mice, we found that compared with Tmod1+/+ mDCs, Tmod1-deficient mDCs exhibited lower surface expression of costimulatory molecules and chemokine receptors and reduced secretion of inflammatory cytokines, suggesting that Tmod1 deficiency retarded DC maturation. Tmod1-deficient mDCs also showed impaired random and chemotactic migration, deteriorated T-cell stimulatory ability, and reduced F-actin content and cell stiffness. Furthermore, Tmod1-deficient mDCs secreted high levels of IFN-β and IL-10 and induced immune tolerance in an experimental autoimmune encephalomyelitis (EAE) mouse model. Mechanistically, Tmod1 deficiency affected TLR4 signaling transduction, resulting in the decreased activity of MyD88-dependent NFκB and MAPK pathways but the increased activity of the TRIF/IRF3 pathway. Rescue with exogenous Tmod1 reversed the effect of Tmod1 deficiency on TLR4 signaling. Therefore, Tmod1 is critical in regulating DC maturation and immune functions by regulating TLR4 signaling and the actin cytoskeleton. Tmod1 may be a potential target for modulating DC functions, a strategy that would be beneficial for immunotherapy for several diseases.

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Alterations of costimulatory molecules and instructive cytokines expressed by dendritic cells in the microenvironment of an endogenous mouse lymphoma

Cancer Immunology Immunotherapy ◽

10.1007/s00262-014-1538-7 ◽

2014 ◽

Vol 63 (5) ◽

pp. 491-499 ◽

Cited By ~ 7

Author(s):

Marcella Naujoks ◽

Jakob Weiß ◽

Tanja Riedel ◽

Nadine Hömberg ◽

Margarethe Przewoznik ◽

...

Keyword(s):

Dendritic Cells ◽

Costimulatory Molecules ◽

Mouse Lymphoma

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Cancer therapy with tumor cell lysate pulsed monocyte-derived dendritic cells in patients with metastastic colon cancer: Improvement by danger signals

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2563 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2563-2563

Author(s):

T. Neβelhut ◽

D. Lorenzen ◽

D. Marx ◽

R. Chang ◽

J. Neβelhut ◽

...

Keyword(s):

Cell Culture ◽

Colon Cancer ◽

Overall Survival ◽

Dendritic Cells ◽

Dendritic Cell ◽

Culture Conditions ◽

Costimulatory Molecules ◽

Danger Signals ◽

Cell Lysate ◽

Tumor Cell Lysate

2563 Background: The prognosis of colon cancers with hematogenous spread remains poor at 12–20 months. We report the use of a dendritic cell based immunotherapy to improve patient survival, especially with cell culture conditions mimicking infection. Methods: After isolating monocytes from the blood of 39 patients with metastasized colon cancer, dendritic cells were generated ex vivo in the presence of recombinant cytokines (IL-4; GM-CSF) and autologous serum. The DC loaded with tumor cell lysate were administered to the patients intradermally. Culture conditions were tested for upregulation of costimulatory molecules, downregulation of IL-10 and upregulation of IL-12 secretion by ELISPOT and fluorescence cytometry. Results: DC vaccination induced a clinical response in 9 (23%) patients with a median overall survival after onset of DC-therapy of 12 months (11–44 months for responders and 1–20 months for non-responders) and 23 months after diagnosis of metastases (16–63 months for responders and 1–23 months for non-responders). These data show that a dendritic cell based immunotherapy may prolong the patients overall survival. However, complete remissions are rare. This can be due to weak stimulation of CTL response due to insufficient antigen presentation, lack of costimulatory molecules as well as secretion of IL-10 rather than IL-12 by the DC’s. Here we could show that Toll-like receptors (TLR) ligands like Poly-I:C or lipopeptides as so called danger signals in combination with interferons can induce an upregulation of costimulatory molecules accompanied by inhibition of IL-10 and induction of IL-12 secretion in vitro. By using these culture conditions we induced a clinical complete remission of liver metastases after failure of standard therapy in one patient (overall survival after onset of DC-therapy 13 months, after diagnosis 24 months). Conclusions: According to Matzinger’s hypothesis an effective immune response occurs only by responding to a danger signal associated with infection or stress. Thus, cell culture condition should be used with TLR ligands mimicking a bacterial or viral infection. In general, a dendritic cell based immunotherapy can be successful in advanced stages of colon cancer patients. [Table: see text]

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