The arginase 1/ornithine decarboxylase pathway suppresses HDAC3 to ameliorate the myeloid cell inflammatory response: implications for retinal ischemic injury.
The arginase 1/ornithine decarboxylase pathway suppresses HDAC3 to ameliorate the myeloid cell inflammatory response: implications for retinal ischemic injury.
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DOI：
10.1038/s41419-023-06147-7
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发表时间：
2023-09-21
影响因子：
9
通讯作者：
Fouda, Abdelrahman Y.
中科院分区：
文献类型：
--
作者：
Shosha, Esraa;Shahror, Rami A.;Morris, Carol A.;Xu, Zhimin;Lucas, Rudolf;McGee-Lawrence, Meghan E.;Rusch, Nancy J.;Caldwell, Ruth B.;Fouda, Abdelrahman Y.
精氨酸酶 1 (A1) 水解氨基酸精氨酸形成 L-鸟氨酸和尿素。鸟氨酸进一步被鸟氨酸脱羧酶（ODC）转化为多胺。我们之前报道过，小鼠髓系 A1 的缺失会加剧缺血/再灌注 (IR) 损伤后的视网膜损伤。此外，A1 治疗可保护野生型小鼠免受视网膜 IR 损伤。 PEG-A1 还可减轻 A1 敲除 (KO) 巨噬细胞在体外的过度炎症反应。在这里，我们试图确定抗炎途径，该途径可赋予巨噬细胞 A1 介导的视网膜 IR 损伤保护作用。眼内压急性升高用于诱导小鼠视网膜IR损伤。多重细胞因子测定显示，IR 损伤后第 5 天，视网膜中炎症细胞因子白细胞介素 1β (IL-1β) 和肿瘤坏死因子 α (TNF-α) 显着增加。在体外，阻断 A1/ODC 通路会增加受刺激巨噬细胞中 IL-1β 和 TNF-α 的产生。此外，A1 治疗减弱了受刺激的巨噬细胞代谢转变为促炎糖酵解表型，而 A1 缺失则具有相反的效果。对在巨噬细胞炎症反应中发挥作用的组蛋白脱乙酰酶 (HDAC) 的筛选表明，A1 缺失或 ODC 抑制会增加 HDAC3 的表达。我们进一步表明，在 A1/ODC 途径缺陷的受刺激巨噬细胞中，HDAC3 参与 TNF-α 的上调，但不参与 IL-1β 的上调。对 HDAC3 KO 巨噬细胞的研究显示，刺激后炎症反应减少，糖酵解表型减少。在体内，IR后第2天，HDAC3在WT视网膜中与小胶质细胞/巨噬细胞共定位，并且在A1缺陷的视网膜中进一步增加。总的来说，我们的数据提供了初步证据，证明 A1 通过 ODC 介导的 HDAC3 和 IL-1β 抑制在巨噬细胞中发挥抗炎作用。总的来说，我们建议增强 A1/ODC 通路并抑制 HDAC3 的干预措施可能为视网膜缺血性疾病的治疗带来治疗益处。
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.
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影响因子：
5.3
作者：
Fouda, Abdelrahman Y.;Eldahshan, Wael;Xu, Zhimin;Lemtalsi, Tahira;Shosha, Esraa;Zaidi, Syed A. H.;Abdelrahman, Ammar A.;Cheng, Paul Ning-Man;Narayanan, S. Priya;Caldwell, R. William;Caldwell, Ruth B.
通讯作者：
Caldwell, Ruth B.
影响因子：
7.3
作者：
Amici SA;Dong J;Guerau-de-Arellano M
通讯作者：
Guerau-de-Arellano M
影响因子：
4.4
作者：
Berger, Samuel;Savitz, Sean I.;Rosenbaum, Daniel M.
通讯作者：
Rosenbaum, Daniel M.
影响因子：
4.4
作者：
Crosson, Craig E.;Mani, Santhosh K.;Menick, Donald R.
通讯作者：
Menick, Donald R.
影响因子：
2.4
作者：
Frank, Tobias;Schlachetzki, Johannes C. M.;Weishaupt, Jochen H.
通讯作者：
Weishaupt, Jochen H.