Brain microglia activation induced by intracranial administration of oligonucleotides and its pharmacological modulation

Sebastiano La Maestra, Guido Frosina, Rosanna T. Micale, Chiara D’Oria, Silvano Garibaldi, Antonio Daga, Alessandra Pulliero, Alberto Izzotti

Research output: Contribution to journalArticlepeer-review


Oligonucleotide overloading results in type I interferonopathies such as the Aicardi-Goutiéres Syndrome, a progressive encephalopathy determined by an immune response against endogenous DNA/RNA molecules. No therapy targeting pathogenic mechanisms is available for affected patients. Accordingly, we set up an in vitro/in vivo experimental model aimed at reproducing the pathogenic mechanisms of type I interferonopathies, in order to develop an effective pharmacological modulation and toxicological alterations caused by intracranial delivery of encapsulated CpG. The in vitro model used Aicardi-Goutiéres Syndrome immortalized lymphocytes activated by interferon I and co-cultured with human astrocytes; lymphocyte neurotoxicity was attenuated by the calcineurin-inhibitor Tacrolimus and by the anti-interferon monoclonal antibody Sifalimumab. The in vivo model was set up in mice by subcutaneous injection of encapsulated CpG oligonucleotides; the immune-stimulating activity was demonstrated by cytometric analysis in the spleen. To mime pathogenesis of type I interferonopathies in the central nervous system, CpG oligonucleotides were administered intracranially in mice. In the brain, CpG overload induced a rapid activation of macrophage-like microglial cells and focal accumulation mononuclear cells. The subcutaneous administration of Tacrolimus and, more potently, Sifalimumab attenuated CpG-induced brain alterations. These findings shed light on molecular mechanisms triggered by oligonucleotides to induce brain damage. Monoclonal antibodies inhibiting interferon seem a promising therapeutic strategy to protect brain in type I interferonopathies.

Original languageEnglish
Pages (from-to)1345-1354
Number of pages10
JournalDrug Delivery and Translational Research
Issue number5
Publication statusPublished - Oct 1 2018


  • Aicardi-Goutiéres Syndrome
  • Brain
  • CpG oligonucleotides
  • Interferonopathies
  • Microglia activation

ASJC Scopus subject areas

  • Pharmaceutical Science


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