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Identifier

000448838

Title

Deciphering the functional link between DNA damage and the innate immune response in macrophages and pancreas

Alternative Title

Διερεύνηση του μοριακού μηχανισμού που συσχετίζει την πρόκληση γενετικών αλλοιώσεωνμε την εκδήλωση ανοσολογικών αποκρίσεων στα μακροφάγα και το πάγκρεας

Author

Χατζηδουκάκη, Ουρανία

Thesis advisor

Ζαφειρόπουλος, Αλέξανδρος
Γαρίνης, Γεώργιος

Reviewer

Τσατσάνης, Χρήστος
Αθανασάκη, Ειρήνη
Σουρβίνος, Γεώργιος
Χαμηλός, Γεώργιος
Νότας, Γεώργιος

Abstract

The functional link between DNA damage, chronic inflammation, tissue degeneration and aging still remains elusive. Using a well-established, progeroid mouse model, which carries an ERCC1-XPF DNA repair defect, we show that persistent DNA damage leads to loss of tissue architecture and fibrosis in Ercc1-/- pancreata. We find that DNA damage-driven R-loops causally contribute to the release and build-up of single-stranded (ss)DNAs in the cytoplasm of cells triggering a viral-like immune response in Ercc1-/- and naturally aged pancreata. To alleviate the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or RNase H nucleases in inflamed Ercc1-/- pancreatic cells. Importantly, treatment of Ercc1-/- animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs ameliorating the proinflammatory response. Thus, DNA damage-driven ssDNA moieties causally contribute to tissue degeneration with advancing age paving the way for novel rationalized intervention strategies against age-related chronic inflammation.

Language

English, Greek

Subject

Aging

ERCC1

Inflamation

R-loops

ssDNA

Γήρανση

Φλεγμονή

Issue date

2022-07-29