Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice.

Autores de CIPF

• Lorena Olivares González

  Autor

• Sheyla Velasco Gomariz

  Autor

• José María Millán Salvador

  Autor

• 

  Regina Rodrigo Nicolás

  Autor

Grupos de Investigación

• Laboratorio de Fisiopatología y Terapias de Enfermedades de la Visión.

  

  Jefe/a de Grupo

  Regina Rodrigo Nicolás

Abstract

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by the progressive and irreversible loss of vision. We previously found that intraperitoneal administration of Adalimumab, a monoclonal anti-TNFa antibody, slowed down retinal degeneration in the murine model of RP, the rd10 mice. The aims of this study were to improve its neuroprotective effect and to deepen understanding of the molecular mechanisms involved in this effect. We analyzed (i) the in vitro effect of Adalimumab on the TNFa-mediated cell death in retinal cells; (ii) the effect of a single intravitreal injection of Adalimumab on retinal degeneration in rd10 mice at postnatal day (P) 23. In vitro studies showed that TNFa induced caspase and poly ADP ribose polymerase (PARP) activation, downregulation of (kinase receptor-interacting protein 1) RIPK1 and upregulation of RIPK3 in retinal cells. Adalimumab reduced cell death probably through the inhibition of caspase 3 activation. In vivo studies suggested that PARP and NLRP3 inflammasome are mainly activated and to a lesser extent caspase-dependent mechanisms in rd10 retinas at P23. Necroptosis seems to be inhibited by the downregulation of RIPK1. Adalimumab prevented from retinal degeneration without affecting caspase -dependent mechanisms but decreasing PARP activation, microglia activation as well as NLRP3 inflammasome.

Keywords

• NLRP3 inflammasome, PARP, TNFa, photoreceptor degeneration