Anti-inflammatory role of MerTK in the RPE independent of diurnal outer segment phagocytosis

MerTK 在 RPE 中的抗炎作用不依赖于昼夜外节吞噬作用

基本信息

  • 批准号:
    10467028
  • 负责人:
  • 金额:
    $ 19.69万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Diurnal RPE phagocytosis is an essential aspect of lifelong continuous renewal of photoreceptor outer segments. Phagocytosis of distal photoreceptor outer segment tips requires activity of RPE surface receptors of the TAM (Tyro3/Axl/MerTK) receptor tyrosine kinase family. In human patients, mutations in the mertk gene cause an unusually severe form of retinitis pigmentosa with blindness in teenage years. The retina in mice and rats lacking MerTK develops normally but rapidly degenerates postnatally, with onset of photoreceptor death before 4 weeks of age. Neuroinflammation and specifically activation and redistribution of retinal microglia has been reported in adult MerTK-deficient animals and has been assumed to be a consequence of photoreceptor distress and debris accumulation caused by lack of daily clearance phagocytosis of spent outer segment tips by the RPE. However, we find that, surprisingly, robust increase in pro-inflammatory cytokines and microglia activation in MerTK-deficient rat and mouse retina precede postnatal onset of photoreceptor outer segment renewal and daily RPE phagocytosis. Moreover, our results show that anti-inflammatory treatment is effective in preventing microglia activation and extending photoreceptor survival and function only if applied at early postnatal age several days prior to the onset of diurnal outer segment renewal and RPE phagocytosis. In wild- type retina, MerTK is expressed early postnatally and mainly by the RPE (and not detected in microglia). This implies that loss of MerTK affects the RPE specifically, directly and before outer segment renewal begins. Thus, all available evidence supports microglia stimulation by MerTK-deficient RPE independently of RPE phagocytic activity and outer segment renewal. Here, we propose highly focused, key proof-of-principle pilot studies to rigorously scrutinize our completely novel concept that lack of MerTK in itself and unrelated to RPE phagocytosis causes RPE cells to release a pro-inflammatory cytokine, which elicits early onset, harmful neuroinflammation that in turn accelerates photoreceptor dysfunction and demise. We will test our hypothesis in 3 independent specific aims. Aim 1 will explore double mutant mice we just generated to test if cytokine is required for neuroinflammation in mertk-/- retina. Aim 2 will explore if inducing cytokine loss in the RPE alone is sufficient to eliminate early postnatal harmful neuroinflammation and whether cytokine mediator must be expressed early postnatally to induce neuroinflammation in mertk-/- retina. Aim 3 will explore polarized, differentiated RPE cell models (primary, unpassaged wild-type and MerTK-deficient RPE and passage 1 human RPE cells) to determine whether MerTK expression and its kinase signaling activity are directly linked mechanistically to cytokine transcription, translation, and/or release by RPE cells. Upon completion, this pilot study will have yielded unambiguous confirmation or disproof of our novel hypothesis and generated in vivo and culture models for large scope mechanistic and pre-translational follow-up.
视网膜色素上皮细胞的昼夜吞噬作用是视网膜色素上皮细胞持续更新的一个重要方面。 片段远端光感受器外节尖端的吞噬作用需要RPE表面受体的活性 TAM(Tyro 3/Axl/MerTK)受体酪氨酸激酶家族的氨基酸序列。在人类患者中, 在梅尔克 基因 会导致一种异常严重的视网膜色素变性,在青少年时期会导致失明。老鼠的视网膜, 缺乏MerTK的大鼠发育正常,但出生后迅速退化,出现感光细胞死亡 在4周大之前。神经炎症,特别是视网膜小胶质细胞的激活和重新分布, 在成年MerTK缺陷动物中有报道,并被认为是感光细胞的结果。 由于缺乏消耗的外节尖端的每日清除吞噬作用而导致的痛苦和碎片积聚 的RPE。然而,我们发现,令人惊讶的是,在促炎细胞因子和小胶质细胞的强劲增加, MerTK缺陷大鼠和小鼠视网膜中感光细胞外节出生后出现之前的激活 更新和每日RPE吞噬作用。而且,我们的研究结果表明抗炎治疗是有效的 在预防小胶质细胞活化和延长感光细胞存活和功能方面, 出生后几天开始的昼夜外节更新和RPE吞噬作用。在野外- 型视网膜中,MerTK在出生后早期表达,主要由RPE表达(在小胶质细胞中未检测到)。这 这意味着MerTK的缺失特异性地、直接地和在外节更新开始之前影响RPE。 因此,所有可用的证据都支持MerTK缺陷型RPE独立于RPE刺激小胶质细胞 吞噬活性和外节更新。在这里,我们提出了高度集中的,关键的原则证明试点 研究严格审查我们完全新颖的概念,即缺乏MerTK本身,与RPE无关 吞噬作用导致RPE细胞释放促炎细胞因子,其促进早期发病,有害 神经炎症,这反过来又加速感光细胞功能障碍和死亡。我们将测试我们的假设 三个独立的具体目标。目的1将探索我们刚刚产生的双突变小鼠,以测试细胞因子是否是 是mertk-/-视网膜神经炎症所必需的。目的2将探索是否诱导细胞因子的损失,在视网膜色素上皮单独是 是否足以消除出生后早期有害神经炎症以及是否必须 在出生后早期表达以诱导mertk-/-视网膜中的神经炎症。目标3将探索两极分化, 分化的RPE细胞模型(原代、未传代的野生型和MerTK缺陷型RPE和第1代 人RPE细胞)以确定MerTK表达和其激酶信号传导活性是否直接相关 在某些实施方案中,细胞因子的表达与RPE细胞的细胞因子转录、翻译和/或释放在机制上相关。完成后,该飞行员 研究将产生明确的证实或反驳我们的新假设,并在体内产生 和文化模式的大范围机械和翻译前的后续行动。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Galectin-3 Promotes Müller Glia Clearance Phagocytosis via MERTK and Reduces Harmful Müller Glia Activation in Inherited and Induced Retinal Degeneration.
  • DOI:
    10.3389/fncel.2022.878260
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    5.3
  • 作者:
    Lew, Deborah S.;McGrath, Morgan J.;Finnemann, Silvia C.
  • 通讯作者:
    Finnemann, Silvia C.
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SILVIA C FINNEMANN其他文献

SILVIA C FINNEMANN的其他文献

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{{ truncateString('SILVIA C FINNEMANN', 18)}}的其他基金

Inflammation in MERTK-dependent retinitis pigmentosa
MERTK 依赖性色素性视网膜炎中的炎症
  • 批准号:
    10743622
  • 财政年份:
    2023
  • 资助金额:
    $ 19.69万
  • 项目类别:
Anti-inflammatory role of MerTK in the RPE independent of diurnal outer segment phagocytosis
MerTK 在 RPE 中的抗炎作用不依赖于昼夜外节吞噬作用
  • 批准号:
    10317323
  • 财政年份:
    2021
  • 资助金额:
    $ 19.69万
  • 项目类别:
Molecular mechanisms of outer segment renewal
外节更新的分子机制
  • 批准号:
    9018962
  • 财政年份:
    2015
  • 资助金额:
    $ 19.69万
  • 项目类别:
Molecular mechanisms of outer segment renewal
外节更新的分子机制
  • 批准号:
    9184560
  • 财政年份:
    2015
  • 资助金额:
    $ 19.69万
  • 项目类别:
The Integrin Ligand MFG-E8 and Photoreceptor Outer Segment Renewal.
整合素配体 MFG-E8 和光感受器外段更新。
  • 批准号:
    7229911
  • 财政年份:
    2006
  • 资助金额:
    $ 19.69万
  • 项目类别:
The Integrin Ligand MFG-E8 and Photoreceptor Outer Segment Renewal.
整合素配体 MFG-E8 和光感受器外段更新。
  • 批准号:
    7026036
  • 财政年份:
    2006
  • 资助金额:
    $ 19.69万
  • 项目类别:
The Integrin Ligand MFG-E8 and Photoreceptor Outer Segment Renewal.
整合素配体 MFG-E8 和光感受器外段更新。
  • 批准号:
    7726317
  • 财政年份:
    2006
  • 资助金额:
    $ 19.69万
  • 项目类别:
Regulation of RPE phagocytosis via avb5 integrin
通过 avb5 整合素调节 RPE 吞噬作用
  • 批准号:
    8238346
  • 财政年份:
    2003
  • 资助金额:
    $ 19.69万
  • 项目类别:
Regulation of RPE phagocytosis via avb5 integrin
通过 avb5 整合素调节 RPE 吞噬作用
  • 批准号:
    7615563
  • 财政年份:
    2003
  • 资助金额:
    $ 19.69万
  • 项目类别:
Regulation of RPE phagocytosis via avb5 integrin
通过 avb5 整合素调节 RPE 吞噬作用
  • 批准号:
    6870166
  • 财政年份:
    2003
  • 资助金额:
    $ 19.69万
  • 项目类别:

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