Prospective Study of Common Variants in<i>CX3CR1</i>and Risk of Macular Degeneration

Schaumberg, Debra A.; Rose, Lynda M.; DeAngelis, Margaret M.; Semba, Richard D.; Hageman, Gregory S.; Chasman, Daniel I.

doi:10.1001/jamaophthalmol.2013.5506

Cited by 22 publications

(18 citation statements)

References 55 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, the research presented here poses important clinical relevance for humans carrying the polymorphic variant CX3CR1 I249/M280 ( CX3CR1 M280 ) estimated in about 20% of the population. These changes in human CX3CR1 decrease FKN affinity (McDermott et al, 2003) and several studies support a role for CX3CR1 M280 in susceptibility to age-related macular degeneration (Tuo et al, 2004; Chan et al, 2005; Brión et al, 2011; Schaumberg et al, 2014). Together, our data suggest a pivotal role for FKN/CX3CR1 signaling in governing microglial responses during insult, and thus modulating CX3CR1 signaling may be relevant alternative approaches to mitigate tissue pathology in the diabetic retina.…”

Section: Discussionmentioning

confidence: 96%

Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy

Mendiola

Garza

Cardona

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Fractalkine (FKN) is a chemokine expressed constitutively by healthy neurons and signals to microglia upon interaction with the FKN receptor, CX3CR1. Signaling between FKN and CX3CR1 transduces inhibitory signals that ameliorate microglial activation and proinflammatory cytokine release in neuroinflammatory conditions. The aim of this study is to determine the mechanisms associated with microglial activation and vascular leakage during diabetic retinopathy (DR) and under conditions of low-level endotoxemia, common in diabetic patients. Utilizing the Ins2Akita strain (Akita), a mouse model of type 1 diabetes, our results show that leakage of the blood-protein fibrin(ogen) into the retina occurs as a result of chronic (4 months) but not acute (1.5 months) hyperglycemia. Conversely, inducing endotoxin-mediated systemic inflammation during acute diabetes resulted in fibrinogen deposition in the retina, a phenotype that was exacerbated in mice lacking CX3CR1 signaling. Systemic inflammation in Cx3cr1−/− mice led to robust perivascular clustering of proliferating microglia in areas of fibrinogen extravasation, and induced IL-1β expression in microglia and astrocytes. Lastly, we determined a protective effect of modulating FKN/CX3CR1 signaling in the diabetic retina. We show that intravitreal (iv) administration of recombinant FKN into diabetic FKN-KO mice, reduced fibrinogen deposition and perivascular clustering of microglia in the retina during systemic inflammation. These data suggest that dysregulated microglial activation via loss of FKN/CX3CR1 signaling disrupts the vascular integrity in retina during systemic inflammation.

show abstract

Section: Discussionmentioning

confidence: 96%

Fractalkine Signaling Attenuates Perivascular Clustering of Microglia and Fibrinogen Leakage during Systemic Inflammation in Mouse Models of Diabetic Retinopathy

Mendiola

Garza

Cardona

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Biochemical studies have suggested that the polymorphic variant CX 3 CR1 I249/M280 exhibits defective adhesive properties, therefore leading to deficits in fractalkine signaling (Faure et al, ; McDermott et al, ). These variants have been associated with multiple neurodegenerative disorders such as age‐related macular degeneration (Chan, Tuo, Bojanowski, Csaky, & Green, ; Schaumberg et al, ), Alzheimer's disease (López‐López, Gelpi, Lopategui, & Vidal‐Taboada, ), and multiple sclerosis (Arli, Irkec, Menevse, Yilmaz, & Alp, ). Based on the evidence of enhanced neuronal damage in the cochlea of CX 3 CR1‐deficient mice, it would be of clinical relevance to dissect the effects of human reference CX 3 CR1 V249/T280 receptor and its polymorphic variant CX 3 CR1 I249/M280 in deaf ears.…”

Section: Discussionmentioning

confidence: 99%

Genetic disruption of fractalkine signaling leads to enhanced loss of cochlear afferents following ototoxic or acoustic injury

Kaur

Ohlemiller

Warchol

2017

J of Comparative Neurology

View full text Add to dashboard Cite

Cochlear hair cells are vulnerable to a variety of insults like acoustic trauma and ototoxic drugs. Such injury can also lead to degeneration of spiral ganglion neurons (SGNs), but this occurs over a period of months to years. Neuronal survival is necessary for the proper function of cochlear prosthetics, therefore, it is of great interest to understand the mechanisms that regulate neuronal survival in deaf ears. We have recently demonstrated that selective hair cell ablation is sufficient to attract leukocytes into the spiral ganglion, and that fractalkine signaling plays a role in macrophage recruitment and in the survival of auditory neurons. Fractalkine (CX CL1), a chemokine that regulates adhesion and migration of leukocytes is expressed by SGNs and signals to leukocytes via its receptor CX CR1. The present study has extended the previous findings to more clinically relevant conditions of sensorineural hearing loss by examining the role of fractalkine signaling after aminoglycoside ototoxicity or acoustic trauma. Both aminoglycoside treatment and acoustic overstimulation led to the loss of hair cells as well as prolonged increase in the numbers of cochlear leukocytes. Lack of CX CR1 did not affect macrophage recruitment after injury, but resulted in increased loss of SGNs and enhanced expression of the inflammatory cytokine interleukin-1β, when compared to mice with intact CX CR1. These data indicate that the dysregulation of macrophage response caused by the absence of CX CR1 may contribute to inflammation-mediated neuronal loss in the deafened ear, suggesting a key role for inflammation in the long-term survival of target-deprived afferent neurons.

show abstract

“…27, 28 However, not all studies have confirmed this association 29, 30 and different studies have identified distinct polymorphisms that may be associated with AMD. 31 Polymorphisms in the genes encoding the chemokine receptor CCR3 32 and chemokine CXCL8 (also known as IL-8), 33, 34 which have been implicated in angiogenesis, 35, 36 have also been associated with AMD. Therefore, AMD has been associated with genetic variants of various inflammatory molecules perhaps suggesting that several inflammatory pathways can lead to the same clinical disease.…”

Section: Immunogenetics Of Amdmentioning

confidence: 99%