Publications by authors named "Aaron den Dekker"

2 Publications

  • Page 1 of 1

Epigenetic stabilization of DC and DC precursor classical activation by TNFα contributes to protective T cell polarization.

Sci Adv 2019 12 4;5(12):eaaw9051. Epub 2019 Dec 4.

Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.

Epigenetic modifications play critical roles in inducing long-lasting immunological memory in innate immune cells, termed trained immunity. Whether similar epigenetic mechanisms regulate dendtritic cell (DC) function to orchestrate development of adaptive immunity remains unknown. We report that DCs matured with IFNγ and TNFα or matured in the lungs during invasive fungal infection with endogenous TNFα acquired a stable TNFα-dependent DC1 program, rendering them resistant to both antigen- and cytokine-induced alternative activation. TNFα-programmed DC1 had increased association of H3K4me3 with DC1 gene promoter regions. Furthermore, MLL1 inhibition blocked TNFα-mediated DC1 phenotype stabilization. During IFI, TNFα-programmed DC1s were required for the development of sustained T1/T17 protective immunity, and bone marrow pre-DCs exhibited TNFα-dependent preprogramming, supporting continuous generation of programmed DC1 throughout the infection. TNFα signaling, associated with epigenetic activation of DC1 genes particularly via H3K4me3, critically contributes to generation and sustenance of type 1/17 adaptive immunity and the immune protection against persistent infection.
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http://dx.doi.org/10.1126/sciadv.aaw9051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6892624PMC
December 2019

Targeting epigenetic mechanisms in diabetic wound healing.

Transl Res 2019 02 10;204:39-50. Epub 2018 Oct 10.

Department of Surgery, University of Michigan, Ann Arbor, Michgan. Electronic address:

Impaired wound healing is a major secondary complication of type 2 diabetes that often results in limb loss and disability. Normal tissue repair progresses through discrete phases including hemostasis, inflammation, proliferation, and remodeling. In diabetes, normal progression through these phases is impaired resulting in a sustained inflammatory state and dysfunctional epithelialization in the wound. Due to their plasticity, macrophages play a critical role in the transition from the inflammation phase to the proliferation phase. Diabetes disrupts macrophage function by impairing monocyte recruitment to the wound, reducing phagocytosis, and prohibiting the transition of inflammatory macrophages to an anti-inflammatory state. Diabetes also impedes keratinocyte and fibroblast function during the later phases resulting in impaired epithelialization of the wound. Several recent studies suggest that altered epigenetic regulation of both immune and structural cells in wounds may influence cell phenotypes and healing, particularly in pathologic states, such as diabetes. Specifically, it has been shown that macrophage plasticity during wound repair is partly regulated epigenetically and that diabetes alters this epigenetic regulation and contributes to a sustained inflammatory state. Epigenetic regulation is also known to regulate keratinocyte and fibroblast function during wound repair. In this review, we provide an introduction to the epigenetic mechanisms that regulate tissue repair and highlight recent findings that demonstrate, how epigenetic events are altered during the course of diabetic wound healing.
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http://dx.doi.org/10.1016/j.trsl.2018.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331222PMC
February 2019