MCS-18, a novel natural product isolated from Helleborus purpurascens, inhibits dendritic cell activation and prevents autoimmunity as shown in vivo using the EAE model

Key PointsCLEC-1 is restricted to CD16− myeloid DCs in human blood and acts as an inhibitory receptor to restrain downstream Th17 activation. CLEC-1–deficient rats highlight an in vivo function for CLEC-1 in preventing excessive T-cell priming and effector Th responses.

Download Full-text

CXCL8 Associated Dendritic Cell Activation Marker Expression and Recruitment as Indicators of Favorable Outcomes in Colorectal Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.667177 ◽

2021 ◽

Vol 12 ◽

Author(s):

Enhao Li ◽

Xiaobao Yang ◽

Yuzhang Du ◽

Guanzheng Wang ◽

David W. Chan ◽

...

Keyword(s):

Colorectal Cancer ◽

Dendritic Cell ◽

Cell Activation ◽

Suppressor Cells ◽

The Cancer Genome Atlas ◽

Dendritic Cell Activation ◽

Antitumor Effects ◽

Activation Markers

Accumulating evidence suggests that tumor-infiltrating immune cells (TICs) in the tumor microenvironment (TME) serve as promising therapeutic targets. CXCL8 (IL-8) may also be a potential therapeutic target in cancer. CXCL8 is a potent chemotactic factor for neutrophils, myeloid-derived suppressor cells (MDSCs) and monocytes, which are considered immunosuppressive components in cancer-bearing hosts. Here, we identified the TME-related gene CXCL8 in a high-ImmuneScore population that contributed to better survival in colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA) database. An integrated gene profile and functional analysis of TIC proportions revealed that the dendritic cell (DC) activation markers CD80, CD83, and CD86 were positively correlated with CXCL8 expression, suggesting that CXCL8 may be functional as antitumor immune response status in the TME. The gene signature was further validated in independent GSE14333 and GSE38832 cohorts from the Gene Expression Omnibus (GEO). To test the differential contributions of immune and tumor components to progression, three CRC cell lines, CT26, MC38 and HCT116, were used. In vitro results suggested no significant growth or survival changes following treatment with an inhibitor of the CXCL8 receptor (CXCR1/2) such as reparixin or danirixin. In vivo treatment with danirixin (antagonists of CXCR2) promoted tumor progression in animal models established with CT26 cells. CXCR2 antagonism may function via an immune component, with CXCR2 antagonist treatment in mice resulting in reduced activated DCs and correlating with decreased Interferon gamma (IFN-γ) or Granzyme B expressed CD8+ T cells. Furthermore, CXCL8 induced DC migration in transwell migration assays. Taken together, our data suggested that targeting the CXCL8-CXCR2 axis might impede DC activation or recruitment, and this axis could be considered a favorable factor rather than a target for critical antitumor effects on CRC.

Download Full-text

Sex-biased ZRSR2 mutations in myeloid malignancies impair plasmacytoid dendritic cell activation and apoptosis

10.1101/2020.10.29.360503 ◽

2020 ◽

Author(s):

Katsuhiro Togami ◽

Sun Sook Chung ◽

Vikas Madan ◽

Christopher M. Kenyon ◽

Lucia Cabal-Hierro ◽

...

Keyword(s):

Dendritic Cell ◽

X Chromosome ◽

Rna Splicing ◽

Cell Activation ◽

Intron Retention ◽

Plasmacytoid Dendritic Cell ◽

Sex Bias ◽

Loss Of Function ◽

Dendritic Cell Activation

ABSTRACTBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDCs). BPDCN occurs at least three times more frequently in men than women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation.STATEMENT OF SIGNIFICANCESex bias in cancer is well recognized but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs dendritic cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.

Download Full-text

Faculty Opinions recommendation of Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished alpha interferon production in vitro.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1115689.571759 ◽

2008 ◽

Author(s):

Scott Sieg ◽

Nicholas Funderburg

Keyword(s):

Human Immunodeficiency Virus ◽

Dendritic Cell ◽

Cell Activation ◽

Plasmacytoid Dendritic Cell ◽

Alpha Interferon ◽

Interferon Production ◽

Dendritic Cell Activation ◽

Immunodeficiency Virus

Download Full-text

Molecular dissection of plasmacytoid dendritic cell activation in vivo during a viral infection

The EMBO Journal ◽

10.15252/embj.201798836 ◽

2018 ◽

Vol 37 (19) ◽

Cited By ~ 13

Author(s):

Elena Tomasello ◽

Karima Naciri ◽

Rabie Chelbi ◽

Gilles Bessou ◽

Anissa Fries ◽

...

Keyword(s):

Dendritic Cell ◽

Viral Infection ◽

Cell Activation ◽

Plasmacytoid Dendritic Cell ◽

Molecular Dissection ◽

Dendritic Cell Activation

Download Full-text

Macrophage and Dendritic Cell Activation and Polarization in Response to Coccidioidesposadasii Infection

Journal of Fungi ◽

10.3390/jof7080630 ◽

2021 ◽

Vol 7 (8) ◽

pp. 630

Author(s):

Anh L. Diep ◽

Susana Tejeda-Garibay ◽

Nadia Miranda ◽

Katrina K. Hoyer

Keyword(s):

Dendritic Cell ◽

Immune Responses ◽

Cell Activation ◽

Immune Cell ◽

Virulent Strain ◽

Macrophage Polarization ◽

Innate Immune ◽

Dendritic Cell Activation ◽

Macrophage Phagocytosis

Coccidioidomycosis is a fungal, respiratory disease caused by Coccidioides immitis and Coccidioides posadasii. The host immune responses that define disease outcome during infection are largely unknown, although T helper responses are required. Adaptive immunity is influenced by innate immunity as antigen-presenting cells activate and educate adaptive responses. Macrophage and dendritic cell (DC) recognition of pathogen surface molecules are critical for Coccidioides clearance. We characterize the broad innate immune responses to Coccidioides by analyzing macrophage and dendritic cell responses to Coccidioides arthroconidia using avirulent, vaccine Coccidioides strain NR-166 (Δcts2/Δard1/Δcts3), developed from parental virulent strain C735. We developed a novel flow cytometry-based method to analyze macrophage phagocytosis to complement traditional image-scoring methods. Our study found that macrophage polarization is blocked at M0 phase and activation reduced, while DCs polarize into proinflammatory DC1s, but not anti-inflammatory DC2, following interaction with Coccidioides. However, DCs exhibit a contact-dependent reduced activation to Coccidioides as defined by co-expression of MHC-II and CD86. In vivo, only modest DC1/DC2 recruitment and activation was observed with avirulent Coccidioides infection. In conclusion, the vaccine Coccidioides strain recruited a mixed DC population in vivo, while in vitro data suggest active innate immune cell inhibition by Coccidioides.

Download Full-text