Abstract
This study examined whether CX3CR1 deficiency altered monocytic cell replenishment dynamics in ocular tissues in the context of radiation chimeras. Long-term effects of irradiation and effects of sublethal irradiation on ocular macrophages were also assessed. Bone marrow from BALB/c Cx 3 cr1 +/gfp or Cx 3 cr1 gfp/gfp mice was used to reconstitute full body irradiated WT mice and donor cell densities in the uveal tract were compared at 4 and 8 weeks post-transplantation. BALB/c and C57BL/6J chimeric mice were examined at 6 months of age to determine strain-related differences in microglial replenishment and radiation sensitivity. A separate cohort of mice were sublethally irradiated (5.5 Gy) and retinal tissue assessed 8 and 12 weeks later. CX3CR1 deficiency altered the early replenishment of monocytes in the posterior iris but not in the iris stroma, choroid or retina. In six month old chimeric mice, there were significantly higher GFP+ cell densities in the uveal tract when compared to non-irradiated 8-12 week old Cx 3 cr1 +/gfp mice. Additionally, MHC Class II expression was upregulated on hyalocytes and GFP+ cells in the peripheral retina and the repopulation of microglia appeared to be more rapid in C57BL/6J mice compared to BALB/c mice. Transient expression of MHC Class II was observed on retinal vasculature in sublethally irradiated mice. These data indicate CX3CR1-deficiency only slightly alters monocyte-derived cell replenishment in the murine uveal tract. Lethal irradiation leads to long-term increase in monocytic cell density in the uveal tract and retinal microglial activation, possibly as a sequelae to local irradiation induced injury. Microglial replenishment in this model appears to be strain dependent.
Highlights
CX3CR1, the sole receptor for the chemokine CX3CL1, or fractalkine, is expressed by monocyte-derived cells including dendritic cells (DCs), natural killer cells and macrophages [1,2]
Using conventional bone marrow (BM) chimeric mice whereby BM from Cx3cr1+/gfp mice was used to reconstitute whole body irradiated BALB/c WT mice (Cx3cr1+/gfp → WT), we demonstrated that donor-derived GFP+ cells begin to repopulate the uveal tract tissues as early as 2 weeks post transplantation, with almost complete replenishment at 8 weeks [33]
The CX3CL1-CX3CR1 pathway is a key mediator of leukocyte chemotaxis and adhesion in human diseases such as atopic dermatitis [40], and in the animal models collageninduced arthritis [41], experimental autoimmune myositis [42] and experimental autoimmune enecephalomyelitis [43]
Summary
CX3CR1, the sole receptor for the chemokine CX3CL1, or fractalkine, is expressed by monocyte-derived cells including dendritic cells (DCs), natural killer cells and macrophages [1,2]. The differential expression of this receptor by tissue resident or ‘non-inflammatory’ macrophages (CX3CR1high and CCR2low) and ‘inflammatory’ macrophages (CX3CR1low CCR2high) [3] has been valuable in elucidating the role of CX3CR1 in different disease models [4,5,6,7]. The regulation of inflammation by CX3CL1/CX3CR1 signaling in central nervous system (CNS) tissues has been well established. CX3CR1 deficiency was associated with greater neuronal cell loss in mouse models of Parkinson’s disease and amyotrophic lateral sclerosis [9]. Data on the role of CX3CL1/CX3CR1 signaling have not provided a clear mechanism of action
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