Reactive microglia and IL1/IL-1R1-signaling mediate neuroprotection in excitotoxin-damaged mouse retina
Reactive microglia and IL1/IL-1R1-signaling mediate neuroprotection in excitotoxin-damaged mouse retina
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DOI：
10.1186/s12974-019-1505-5
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发表时间：
2019-06-06
影响因子：
9.3
通讯作者：
Fischer, Andy J.
中科院分区：
文献类型：
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作者：
Todd, Levi;Palazzo, Isabella;Fischer, Andy J.
背景在不同的中枢神经系统疾病模型中，小胶质细胞和炎症对神经元存活有特定的影响。在此，我们调查如何炎症介质，包括小胶质细胞，白细胞介素1 β（IL-1），并通过白细胞介素1受体1型（IL-1 R1）的信号，影响视网膜神经元的存活率在响应兴奋性损伤。MethodsExcitotoxic视网膜损伤诱导通过眼内注射NMDA。通过免疫组织化学评估小胶质细胞表型和神经元存活。进行单细胞RNA测序以获得转录组谱。用氯膦酸盐脂质体或PLX 5622消融小胶质细胞。视网膜与IL-1 NMDA损伤和细胞死亡进行了评估，在野生型，IL-1 R1空小鼠，和小鼠表达IL-1 R1只在astrocytes. ResultsNMDA诱导的损伤包括神经元细胞死亡，小胶质细胞的反应，促炎细胞因子的上调，与IL-1信号在不同类型的视网膜神经元和神经胶质细胞的基因。在星形胶质细胞、内皮细胞、一些Muller神经胶质细胞和OFF双极细胞中，IL-1受体IL-1 R1的表达是明显的。用氯膦酸盐脂质体或Csf 1 r拮抗剂（PLX 5622）消融小胶质细胞导致兴奋性毒素损伤视网膜中细胞死亡增加和神经元存活减少。外源性IL-1刺激小胶质细胞的增殖和反应性，在没有损伤的情况下，减少受损视网膜中垂死细胞的数量，并增加损伤后神经元的存活。IL-1未能提供神经保护的IL-1 R1-null视网膜，但IL-1介导的神经保护被救出时，IL-1 R1的表达恢复在astrocytes.ConclusionsWe的结论，反应性小胶质细胞提供保护视网膜神经元，因为没有小胶质细胞是有害的生存。我们提出，至少部分，小胶质细胞的生存影响的影响可能介导的IL-1，IL-1 R1，小胶质细胞和其他大胶质细胞的相互作用。
BackgroundMicroglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.MethodsExcitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1 prior to NMDA damage and cell death was assessed in wild type, IL-1R1 null mice, and mice expressing IL-1R1 only in astrocytes.ResultsNMDA-induced damage included neuronal cell death, microglial reactivity, upregulation of pro-inflammatory cytokines, and genes associated with IL1-signaling in different types of retinal neurons and glia. Expression of the IL1 receptor, IL-1R1, was evident in astrocytes, endothelial cells, some Muller glia, and OFF bipolar cells. Ablation of microglia with clodronate liposomes or Csf1r antagonist (PLX5622) resulted in elevated cell death and diminished neuronal survival in excitotoxin-damaged retinas. Exogenous IL1 stimulated the proliferation and reactivity of microglia in the absence of damage, reduced numbers of dying cells in damaged retinas, and increased neuronal survival following an insult. IL1 failed to provide neuroprotection in the IL-1R1-null retina, but IL1-mediated neuroprotection was rescued when expression of IL-1R1 was restored in astrocytes.ConclusionsWe conclude that reactive microglia provide protection to retinal neurons, since the absence of microglia is detrimental to survival. We propose that, at least in part, the survival-influencing effects of microglia may be mediated by IL1, IL-1R1, and interactions of microglia and other macroglia.