Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice.

Fecha de publicación: 01/10/2020 Fecha Ahead of Print: 20/08/2020

Autores de IIS La Fe

José María Millán Salvador

Autor
Regina Rodrigo Nicolás

Autor

Participantes ajenos a IIS La Fe

Olivares-González L
Velasco S

Grupos

Biomedicina Molecular, Celular y Genómica

Leader

José María Millán Salvador
Unidad mixta de investigación en enfermedades raras (CIPF)

Leader

José María Millán Salvador

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.

Datos de la publicación

ISSN/ISSNe:: 0892-6638, 1530-6860
Tipo:: Article
Páginas:: 13839-13861
DOI:: 10.1096/fj.202000044RR
Factor de Impacto:: 1,709 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Olivares-González L:: Pathophysiology and Therapies for Vision Disorders, Principe Felipe Research Center, Valencia, Spain
Velasco S:: Pathophysiology and Therapies for Vision Disorders, Principe Felipe Research Center, Valencia, Spain
Millán JM:: Rare Diseases Networking Biomedical Research Centre (CIBERER), Madrid, Spain

Instituto de Investigación. Joint Unit on Rare Diseases CIPF-La Fe, Valencia, Spain

Instituto de Investigación. Molecular, Cellular and Genomic Biomedicine, Health Research Institute La Fe, Valencia, Spain
Rodrigo R:: Pathophysiology and Therapies for Vision Disorders, Principe Felipe Research Center, Valencia, Spain

Rare Diseases Networking Biomedical Research Centre (CIBERER), Madrid, Spain

Instituto de Investigación. Joint Unit on Rare Diseases CIPF-La Fe, Valencia, Spain

Keywords

NLRP3 inflammasome, PARP, TNFa, photoreceptor degeneration

Proyectos asociados

CARACTERIZACION MOLECULAR DE PACIENTES CON SINDROME DE USHER. ESTUDIO DE LOS GENES RESPONSABLES: CDH23 Y PCDH15 Y CANDIDATOS: WHRN, CXADR Y PDZK7

Investigador Principal: JOSÉ MARÍA MILLÁN SALVADOR

PI07/0558 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2008

MOLECULAR MAECHANISMS OF RETINAL DEGENERATION IN HUMANS WITH RETINITIS PIGMENTOSA. ROLE OF INFLAMMATION, OXIDATIVE STRESS AND GLIAL ACTIVATION

CP09/00118 (MIGUEL SERVET) . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2010

RED DE BIOBANCOS (BIOBANCOS)

RD09/0076/00021 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2010

CARACTERIZACION MOLECULAR EN PACIENTES CON SINDROME DE USHER TIPO I MEDIANTE LA APLICACION DE LAS TECNICAS DE SECUENCIACION Y CGH-ARRAY EN GENES RESPONSABLES Y GENES CANDIDATOS

FPU_AP2009-3344 . MINISTERIO DE EDUCACION, CULTURA Y DEPORTE; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2010