title: PARP-1 inhibition prevents CNS migration of dendritic cells during EAE, suppressing the encephalitogenic response and relapse severity.
abstract: BACKGROUND
  Pharmacological inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are currently evaluated in clinical trials for various malignancies but, interestingly, also proved of remarkable efficacy in preclinical models of autoimmune disorders including experimental autoimmune encephalomyelitis (EAE).
  
  
  OBJECTIVE
  The objectives of the study were to determine molecular mechanisms underlying suppression of the encephalitogenic response by these drugs; likewise, whether clinically-relevant post-treatment paradigms with PARP-1 inhibitors could prevent EAE relapses.
  
  
  METHODS
  Adopted both in vitro techniques (bone marrow-derived cultured DC) as well as in vivo models of chronic or relapsing-remitting (RR) EAE.
  
  
  RESULTS
  We report that two structurally unrelated PARP-1 inhibitors negatively regulated NFκB activation, as well as maturation, cytokine production and APC function of cultured mouse bone marrow-derived dendritic cells (DCs). PARP-1 inhibitors also reduced the number and APC function of DCs migrating in the draining lymph nodes of ovalbumin-immunized mice. In C57Bl mice with chronic EAE or SJL mice with RR EAE, pharmacological inhibition of PARP-1 reduced CNS DC migration and demyelination as well as neurological impairment to an extent similar to that achieved with the potent immunosuppressant cyclosporine A. Remarkably, PARP-1 inhibitors injected after the first phase of disease reduced relapse incidence and severity, as well as the spinal cord number of autoreactive Th17 cells. Under this clinically-relevant treatment paradigm, PARP inhibitors also suppressed epitope spreading of the encephalitogenic response.
  
  
  CONCLUSIONS
  Overall, data underscore the potential relevance of PARP-1 inhibitors to MS therapy and suppression of autoimmunity.
authors.affiliation: Department of Pharmacology, University of Florence, Florence, Italy. leonardo.cavone@unifi.it
authors.forename: Leonardo
authors.initials: L
authors.lastname: Cavone
authors.forename: Alessandra
authors.initials: A
authors.lastname: Aldinucci
authors.forename: Clara
authors.initials: C
authors.lastname: Ballerini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Biagioli
authors.forename: Flavio
authors.initials: F
authors.lastname: Moroni
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarugi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D015551:Autoimmunity / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010047:Ovalbumin / Q000276:immunology; D010616:Phenanthrenes / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012008:Recurrence; D012720:Severity of Illness Index; D058504:Th17 Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D013997:Time Factors
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D016328:NF-kappa B; D018696:Neuroprotective Agents; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D010047:Ovalbumin; C040601:phenanthridone; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases