Exploring the role of CXCL4 in modulating immune responses triggered by monocyte-derived dendritic cells: beyond what the eyes can see

Sandra Cristina Silva Cardoso

    Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)


    Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder characterised by vasculopathy, immune cell dysfunction, antibodies production and aberrant deposition of extracellular matrix components (ECM), such as fibronectin. Changes in frequency and activation of platelets and immune cells are implicated in aberrant inflammatory and fibrotic responses associated with the pathology of SSc.
    CXCL4 is a chemokine released by activated platelets and immune cells. Our group and others have shown that CXCL4 levels are increased of in circulation and in skin of SSc patients.
    In this thesis we investigated whether the exposure to CXCL4 potentiates pro-inflammatory and pro-fibrotic responses by monocyte-derived dendritic cells (moDCs). Additionally we explored the underlying molecular mechanisms implicated in the reprogramming of moDC phenotype and function by CXCL4.
    We found that CXCL4 primes moDCs to a semi-mature phenotype and morphology, amplifies aberrant TLR3-mediated responses and potentiates the activation of autologous and antigen specific T-cell responses. We unrevealed that CXCL4-mediated immunogenic responses are regulated at the transcriptional, post-transcriptional and epigenetic level. Using data driven gene regulatory network analyses, we showed that CXCL4 modulates pro-inflammatory and pro-fibrotic responses via key transcription regulators, such as CIITA (Class II Major Histocompatibility Complex Transactivator) and IRF8 (Interferon Regulatory Factor 8). Additionally, we unrevealed that aberrant pro-inflammatory cytokine production upon TLR3-mediated stimulation relies in part on enhanced cytokine mRNA stability dictated by the inactivation of tristetrapolin (TTP), an AU-rich element binding protein (ARE-BP).
    Altogether, this thesis highlights the role of CXCL4 in reprogramming moDC phenotype and function and opens new avenues for therapeutic intervention
    Original languageEnglish
    Awarding Institution
    • University Medical Center (UMC) Utrecht
    • Radstake, T.R.D.J., Primary supervisor
    • Pandit, A., Co-supervisor
    • Boes, Marianne, Co-supervisor
    Award date9 Dec 2019
    Place of Publication[Utrecht]
    Print ISBNs978-94-93184-15-2
    Publication statusPublished - 9 Dec 2019


    • Systemic Sclerosis
    • CXCL4
    • Dendritic cells
    • T cells
    • Innate and adaptive Immunity
    • Transcrisptomics
    • DNA methylation
    • Transcription factors
    • RNA stability
    • Immunogenic responses


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