Monocyte-derived macrophages exacerbate cone degeneration in a mouse model of retinitis pigmentosa

Abstract

Purpose : Although the disease of retinitis pigmentosa (RP) is initiated with genetic mutations, accumulating body of evidence indicate that chronic inflammation modulates the disease progression, especially in the late cone-degenerating phase. We recently reported that the serum high sensitivity C-reactive protein (hs-CRP) is elevated in RP patients and higher hs-CRP is associated with faster deterioration of central visual function. Using a mouse model of RP and blood samples of RP patients, we here investigated the possible involvement of monocyte-derived macrophages (Mo-MFs) in the pathogenesis of RP.

Methods : In animal experiments, C57BL6/J (WT) mice, rd10 mice, a RP model with Pde6bmutation, rd10 mouse deficient for Ccl2 gene (rd10: Ccl2^-/-mice; Ccl2 is a key chemokine regulating monocyte recruitment via Ccl2/Ccr2 axis) were used. The peripheral blood and retina samples of each mouse were obtained,and were analyzed with flowcytometry. Cone photoreceptor cells were stained with peanut agglutinin lectin in the whole-mount retinas. Twenty-five RP patients <40 years old and 19 age- and gender-matched healthy subjects were included. The peripheral blood samples of each subject were analyzed with flowcytometry, and the relations between the inflammatory subset and the changes of visual function (e.g. visual acuity and sensitivity in the static perimetry test.

Results : In rd10 mice, the percentage of inflammatory monocytes (Imo; Ly6C^highCCR2⁺ CX3CR1⁺subset) in the peripheral blood was increased at postnatal day 21 (P21) compared with WT mice (P= 0.03). CD45^lowCD11c^lowresident microglia (Re-MG) as well as CD45^highCD11c^highMo-MFs were substantially increased in rd10 retina compared with WT retina at P21, P31 and P42 (all P< 0.05). In rd10: Ccl2^-/-mice, IMo in the peripheral blood and Mo-MFs in the retina were clearly decreased compared with rd10 mice at P21 and P31 (P<0.05), while Re-MG subset was not different between rd10 and rd10: Ccl2^-/-mice. The cone cell density was significantly preserved at P52 rd10: Ccl2^-/-mice compared with rd10 mice (P<0.05). In human blood samples, the higher percentage of CD14⁺⁺CD16 ⁺Mo which expressed both CCR2 and CX3CR1were associated with faster deterioration of visual sensitivity in RP patients.

Conclusions : These data suggest that Mo-MFs exacerbates cone degeneration in RP, and identify IMo and Mo-MFs as potential targets to developing anti-inflammatory therapy for RP.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.