Gene-environment Interaction: Dysregulation Of Pyrin, The Familial Mediterranean Fever Protein, Exacerbates Endotoxin-induced Uveitis In Mice

Abstract

Purpose: : Pyrin (encoded by the gene MEFV) is the cause of the recessively inherited autoinflammatory disorder, familial Mediterranean fever (FMF). Recent reports support the involvement of pyrin in other inflammatory diseases including Behcet’s disease, multiple sclerosis, ankylosing spondylitis, and Crohn’s disease. Pyrin is normally involved in regulation of inflammasome activation and IL-1-beta production. Given the importance of IL-1-beta in disease and the association of uveitis with systemic autoinflammatory disorders linked with pyrin, we sought to elucidate the functional consequences of the pathogenic, variant V726A pyrin on endotoxin-induced uveitis.

Methods: : Knock-in mice containing the V726A mutation or littermate controls (S129/C57Bl/6 chimeras) were observed without intervention or were administered an intravitreal injection of 250 ng lipopolysaccharide (LPS) in one eye and saline in the contralateral eye. Ocular inflammation was assessed histologically 24h later. Circulating neutrophils were quantified by flow cytometric analysis. Arthritis was assessed histologically and by near-infrared whole body imaging.

Results: : Carriers with 1 copy of the mutation appear phenotypically normal. However, mice with 2 copies of the mutation spontaneously developed neutrophilia, arthritis and conjunctivitis akin to patients with FMF. While the MEFV mutation did not predispose to spontaneous onset of uveitis, it did render mice hypersensitive to endotoxin-induced uveitis with mice developing pan-uveitis with corneal, iris, limbal, retinal, scleral and episcleral involvement. Inflammation was predominantly neutrophilic, with neutrophils infiltrating the subretinal space which coincided with dilated vessels and hemorrhaging within the retina.

Conclusions: : Our data provide insight into how dysregulation of pyrin may influence susceptibility to uveitis. The model demonstrates a robust gene-environment interaction that results in disease far greater than that induced by either the gene or the environmental factor (i.e. LPS in this case) alone.

Keywords: uveitis-clinical/animal model • inflammation