酶精氨酸酶1（A1）通过水解氨基酸精氨酸形成L-鸟氨酸和尿素。鸟氨酸随后由鸟氨酸脱羧酶（ODC）酶转化为多胺。我们以前报道称，在小鼠中删去髓系A1会加重缺血/再灌注（IR）损伤后的视网膜损伤。此外，A1的治疗也能保护野生型小鼠免受视网膜IR损伤的伤害。PEG-A1还可以减轻A1基因敲除（KO）巨噬细胞在体外的过度炎症反应。在这里, 我们旨在确认巨噬细胞A1介导的抗炎途径，在视网膜IR损伤中的保护作用。我们使用急性眼压增高来诱导小鼠视网膜IR损伤。多重细胞因子分析表明，在IR损伤后的第5天，视网膜中的炎症细胞因子白细胞介素1β（IL-1β）和肿瘤坏死因子α（TNF-α）显著增加。在体外，阻断A1/ODC途径会增加刺激巨噬细胞产生IL-1β和TNF-α。此外，A1处理减弱了刺激巨噬细胞代谢转变为促炎性的糖酵解表型，而A1敲除则产生了相反的效果。筛选对巨噬细胞炎症反应发挥作用的组蛋白去乙酰化酶（HDACs）显示，A1敲除或ODC抑制增加了HDAC3的表达。我们进一步证明了HDAC3在A1/ODC途径缺陷巨噬细胞中上调TNF-α而不是IL-1β的作用。研究HDAC3编码基因敲除的巨噬细胞显示，其刺激后的炎症反应减弱，并且在刺激后表现出较少的糖酵解表型。在体内，HDAC3与微胶质细胞/巨噬细胞在IR后的第2天共定位于WT的视网膜中，并在A1缺陷的视网膜中进一步增加。综上所述，我们的数据初步证明，A1通过ODC介导的抑制HDAC3和IL-1β的作用，在巨噬细胞中产生其抗炎效果。综合我们的观点，在视网膜缺血性疾病的治疗中，增强A1/ODC途径并抑制HDAC3可能具有治疗效益。©2023年。作者（们）。

The enzyme arginase 1 (A1) hydrolyzes the amino acid arginine to form L-ornithine and urea. Ornithine is further converted to polyamines by the ornithine decarboxylase (ODC) enzyme. We previously reported that deletion of myeloid A1 in mice exacerbates retinal damage after ischemia/reperfusion (IR) injury. Furthermore, treatment with A1 protects against retinal IR injury in wild-type mice. PEG-A1 also mitigates the exaggerated inflammatory response of A1 knockout (KO) macrophages in vitro. Here, we sought to identify the anti-inflammatory pathway that confers macrophage A1-mediated protection against retinal IR injury. Acute elevation of intraocular pressure was used to induce retinal IR injury in mice. A multiplex cytokine assay revealed a marked increase in the inflammatory cytokines interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) in the retina at day 5 after IR injury. In vitro, blocking the A1/ODC pathway augmented IL-1β and TNF-α production in stimulated macrophages. Furthermore, A1 treatment attenuated the stimulated macrophage metabolic switch to a pro-inflammatory glycolytic phenotype, whereas A1 deletion had the opposite effect. Screening for histone deacetylases (HDACs) which play a role in macrophage inflammatory response showed that A1 deletion or ODC inhibition increased the expression of HDAC3. We further showed the involvement of HDAC3 in the upregulation of TNF-α but not IL-1β in stimulated macrophages deficient in the A1/ODC pathway. Investigating HDAC3 KO macrophages showed a reduced inflammatory response and a less glycolytic phenotype upon stimulation. In vivo, HDAC3 co-localized with microglia/macrophages at day 2 after IR in WT retinas and was further increased in A1-deficient retinas. Collectively, our data provide initial evidence that A1 exerts its anti-inflammatory effect in macrophages via ODC-mediated suppression of HDAC3 and IL-1β. Collectively we propose that interventions that augment the A1/ODC pathway and inhibit HDAC3 may confer therapeutic benefits for the treatment of retinal ischemic diseases.© 2023. The Author(s).