La dégénérescence des photorécepteurs dans la pathologie de la dégénérescence maculaire liée à l'âge (DMLA) est associée à une infiltration et accumulation des phagocytes mononuclées (PM). Nous avons montré précédemment que les souris déficientes pour Cx3cr1 développent une accumulation des PM sous-rétiniens avec l'âge et avec le stress, qui est associée une dégénérescence des photorécepteurs. Dans le cerveau, la déficience de Cx3cr1 dans les PM induit une augmentation de la mort des neurones via IL-1β. La raison de l'augmentation de la sécrétion d'IL-1β par les PM déficients en Cx3cr1 reste inconnue. Nous montrons que les PM déficients en Cx3cr1 surexpriment le récepteur P2RX7 qui stimule la maturation et la sécrétion d'IL-1β. L'inhibition de P2RX7 et d'Il-1β diminuent la mort des photorécepteurs dans un modèle de cocultures de monocytes/rétine et avec le modèle d'illumination in vivo. Nos résultats suggèrent que l'inhibition de P2RX7 ou d'Il-1β peut diminuer l'inflammation sous-rétinienne qui est associée à la mort des photorécepteurs dans la pathologie de la DMLA, où il n'existe aucun traitement à l'heure actuelle pour la forme atrophique. / Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1 -deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1 -deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1 β secretion from Cx3cr1 -deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1 -deficient mice, has not been elucidated. Here we show that Cx3cr1 -deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1_β inhibition efficiently blunted Cx3cr1 -MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light induced subretinal inflammation of Cx3cr1 -deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists.

Introduction: Canadian First Nations experience a significantly higher rate of Mycobacterium tuberculosis (MTB) infection than non-Indigenous Canadians. Th17 cells are a subset of CD4+ T cells that are distinguished by their production of Interleukin-17A (IL-17A), an important cytokine for defense against mycobacteria. IL-17 is a primary contributor to the formation and stabilization of the lung granuloma, a biological containment vessel to protect the host from tuberculosis (TB). Past research with First Nations people has identified single nucleotide polymorphisms (SNPs) in the Th1 and Th2 immune pathways may affect their disease risk. However, SNPs in key Th17 related genes and the P2RX7 gene have not been explored in First Nations despite their important role against infectious diseases. Hypothesis: This research hypothesizes that distinct First Nations groups (Dene, Cree and Saulteaux) will have a different frequencies of SNPs in the key Th17 immunity related genes (IL-17A, IL-17AR, IL-23R, and IFN-γR) and the P2RX7 gene, as compared to a non-Indigenous Canadian group. Methods: SNP profiles (IL-17A rs2275913, IL-17RA rs4819554, IL-23R rs10889677, IFN-γR rs2234711 and P2RX7 rs3751143) were identified through literature research and the NCBI database was used for identifying gene motifs, primer locations and Restriction Enzyme cut sites. Polymerase Chain Reaction and Restriction Fragment Length Polymorphism analysis was performed on and visualized on agarose gel to determine specific allele frequencies. Four different Manitoba First Nations communities; the Northern Dene (Dene 1 N=69. Dene 2 N=52), Central Cree (N=46), and Southern Saulteaux (N=56), participated in this research and their SNP profiles were compared to a non-Indigenous Canadian cohort (N=99). Results: Allele frequencies for IL-17A were statistically different for every First Nation community when compared to the non-Indigenous cohort (Dene 1 p=0.0043, Dene 2 p=0.0000, Cree p=0.0001, Saulteaux p=0.0000). Allele frequencies for IL-17RA were statistically different for every First Nation community except Saulteaux when compared to the non-Indigenous cohort (Dene 1 p=0.0000, Dene 2 p=0.0028, Cree p=0.0000). Allele frequencies for IL-23R were statistically different for Dene 1 and Saulteaux community when compared to the non-Indigenous cohort (Dene 1 p=0.0002, Saulteaux p=0.0000). Allele frequencies for IFN-R were statistically different for Cree community when compared to the non-Indigenous cohort (Cree p=0.0026). Allele frequencies for P2RX7 were statistically different for both Dene communities when compared to the non-Indigenous cohort (Dene 1 p=0.0000, Dene 2 p=0.0000). Conclusions: An effective Th17 response is required to bring Th1 cells to infected tissues and to balance inflammatory responses. Functional SNPs may compromise an appropriate immune response and contribute to disease. This study demonstrate that the non-Indigenous population maintained a significantly different genetic profile when compared to the First Nations populations. / October 2016