Sherman Joe, Burgstaler Laura, Li Yunan, Roehrich Heidi, Gregerson Dale S, McPherson Scott W
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States.
Invest Ophthalmol Vis Sci. 2025 Aug 1;66(11):26. doi: 10.1167/iovs.66.11.26.
We reported earlier that induction of spontaneous autoimmune uveoretinitis (SAU) correlated with the recruitment of circulating antigen-presenting cells (APCs) into the retina. Here, we investigated the role of resident retinal APCs on the course of SAU.
R161H+/- mice (B10.RIII), which spontaneously and rapidly develop severe autoimmune uveoretinitis, were crossed with CD11cDTR/GFP mice (B6/J). R161H+/- mice on the B6/J background develop slower, less severe SAU than R161H+/--B10.RIII mice, allowing assessment of disease development relative to the depletion or activation of retinal or systemic APCs. The course of SAU was established in a cohort of control R161H+/- × CD11cDTR/GFP F1 mice and then reanalyzed in test cohorts following treatment with diphtheria toxin or stimulation by optic nerve crush (ONC) injury. Analysis was done by retinal imaging, flow cytometry, and histology.
Systemic depletion of APCs halted the progression of SAU in R161H+/- × CD11cDTR/GFP F1 mice and, if commenced early in the disease process, would reduce SAU severity. However, following depletion of APCs specifically from the retina, SAU in R161H+/- × CD11cDTR/GFP F1 mice progressed in a manner similar to that of control mice. In contrast, SAU in R161H+/- × CD11cDTR/GFP F1 mice was exacerbated following the activation of retinal APCs by ONC.
Our observations that local depletion of retinal APCs failed to inhibit SAU progression and that depletion of circulating APCs not only limited SAU progression but also, under defined circumstances, reduced clinical SAU support the idea that circulating APCs are crucial for the induction and progression of SAU.
我们之前报道过，自发性自身免疫性葡萄膜视网膜炎（SAU）的诱发与循环抗原呈递细胞（APC）向视网膜的募集有关。在此，我们研究了视网膜常驻APC在SAU病程中的作用。
自发且迅速发展为严重自身免疫性葡萄膜视网膜炎的R161H+/-小鼠（B10.RIII）与CD11cDTR/GFP小鼠（B6/J）杂交。与R161H+/- - B10.RIII小鼠相比，B6/J背景的R161H+/-小鼠SAU发展较慢且病情较轻，这使得我们能够相对于视网膜或全身APC的耗竭或激活来评估疾病发展情况。在一组对照R161H+/-×CD11cDTR/GFP F1小鼠中确定SAU病程，然后在用白喉毒素治疗或视神经挤压（ONC）损伤刺激后的测试组中重新分析。通过视网膜成像、流式细胞术和组织学进行分析。
全身APC耗竭使R161H+/-×CD11cDTR/GFP F1小鼠的SAU进展停止，并且如果在疾病过程早期开始，会降低SAU严重程度。然而，在从视网膜特异性耗竭APC后，R161H+/-×CD11cDTR/GFP F1小鼠的SAU以与对照小鼠相似的方式进展。相比之下，ONC激活视网膜APC后，R161H+/-×CD11cDTR/GFP F1小鼠的SAU会加剧。
我们的观察结果表明，视网膜APC的局部耗竭未能抑制SAU进展，而循环APC的耗竭不仅限制了SAU进展，而且在特定情况下还降低了临床SAU，这支持了循环APC对SAU的诱发和进展至关重要的观点。
