Investigating the thermal biology of inflammasomes - is NLRP3 a thermosensor?

研究炎症小体的热生物学 - NLRP3 是热传感器吗？

• 批准号: BB/V016741/1
• 负责人: Rebecca Coll
• 金额: $ 57.35万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV016741%2F1
• 关键词: Investigating; thermal; biology; inflammasomes; NLRP3

Inflammation is a natural response to infection and injury and is an essential part of our immune response which protects us from invading microbes. For example, when we get a cut on our finger, the redness, heat and pain that we feel actually helps us clear the infection and heal the wound. Inflammation is therefore generally beneficial to us. However, it is becoming clear that inflammation also plays a negative role in many diseases, particularly those associated with ageing and metabolism. In disorders such as arthritis, liver disease, and Alzheimer's disease, this damaging inflammation causes disease progression. It is therefore imperative that we study the molecular mechanisms of inflammation as this informs our understanding of these prevalent diseases which are a huge burden on our health service and our society. The main objective of our research proposal is to discover how a protein complex called the inflammasome is regulated or fine-tuned during the immune response. Inflammasomes, and specifically one type of inflammasome called NLRP3, are one of the most potent causes of inflammation in our immune cells. Our preliminary experiments have shown that increased temperatures, which are similar to those which occur during fever, seem to specifically block the inflammation caused by inflammasomes. This suggests that the immune response has developed a way to limit excessive or harmful inflammation triggered by these inflammasomes. We want to understand how this happens and the first aim of our study is to define how heat shock proteins (HSPs), which are naturally induced by high temperatures, influence inflammasome activity. To do this we will perform experiments using immune cells called macrophages which express high levels of inflammasome proteins. We will use chemical inhibitors of HSPs to study how HSP function affects inflammasome-dependent inflammation and the interactions of inflammasome proteins. Our next focus will be the inflammasome sensor protein NLRP3. We have developed a new idea that NLRP3 itself can sense changes in temperature. Changes in temperature are a physiological stress faced by all organisms and as NLRP3 is able to sense many types cellular stress it could thus also be a thermosensor. To investigate this idea, we will use advanced techniques such as quantitative mass spectrometry to determine how NLRP3 behaves when cells are heated to fever range temperatures. We suspect that how NLRP3 interacts with other proteins will change with changes in temperature. Our third objective is to understand how mutant forms of NLRP3 are activated by cold temperatures. Mutations in NLRP3 cause a rare inherited disease called familial cold autoinflammatory syndrome (FCAS). FCAS patients experience inflammatory symptoms such as skin rashes and fever when they are exposed to cold temperatures. No one yet understands how this unusual response occurs and so we will develop new cell models to study the mechanisms of this disease. We will then study the behaviour of FCAS NLRP3 in these cells using mass spectrometry and other biochemical techniques.Ultimately, new knowledge about the function and regulation of inflammasomes and NLRP3 could help the development of new drugs for people suffering with inflammatory diseases.

炎症是对感染和损伤的自然反应，是保护我们免受微生物入侵的免疫反应的重要组成部分。例如，当我们的手指被割伤时，我们感受到的红、热和疼痛实际上可以帮助我们清除感染并治愈伤口。因此，炎症通常对我们有益。然而，越来越明显的是，炎症在许多疾病中也发挥着负面作用，特别是那些与衰老和新陈代谢相关的疾病。在关节炎、肝病和阿尔茨海默病等疾病中，这种破坏性炎症会导致疾病进展。因此，我们有必要研究炎症的分子机制，因为这有助于我们了解这些流行疾病，这些疾病给我们的卫生服务和社会带来了巨大的负担。我们研究计划的主要目标是发现一种称为炎症小体的蛋白质复合物在免疫反应过程中如何受到调节或微调。炎症小体，特别是一种称为 NLRP3 的炎症小体，是我们免疫细胞炎症的最有力原因之一。我们的初步实验表明，与发烧期间发生的温度升高类似，温度升高似乎可以特异性阻止炎症体引起的炎症。这表明免疫反应已经发展出一种方法来限制这些炎症体引发的过度或有害炎症。我们想了解这是如何发生的，我们研究的首要目的是确定由高温自然诱导的热休克蛋白（HSP）如何影响炎症小体活动。为此，我们将使用称为巨噬细胞的免疫细胞进行实验，这些细胞表达高水平的炎性体蛋白。我们将使用热休克蛋白的化学抑制剂来研究热休克蛋白的功能如何影响炎症小体依赖性炎症以及炎症小体蛋白的相互作用。我们的下一个重点将是炎症小体传感器蛋白 NLRP3。我们提出了一个新想法：NLRP3 本身可以感知温度的变化。温度变化是所有生物体面临的一种生理应激，由于 NLRP3 能够感知多种类型的细胞应激，因此它也可以成为一种热传感器。为了研究这个想法，我们将使用定量质谱等先进技术来确定当细胞被加热到发烧范围温度时 NLRP3 的行为。我们怀疑 NLRP3 与其他蛋白质相互作用的方式会随着温度的变化而改变。我们的第三个目标是了解低温如何激活 NLRP3 的突变形式。 NLRP3 突变会导致一种罕见的遗传性疾病，称为家族性感冒自身炎症综合征 (FCAS)。 FCAS 患者在暴露于低温时会出现皮疹和发烧等炎症症状。目前还没有人了解这种不寻常的反应是如何发生的，因此我们将开发新的细胞模型来研究这种疾病的机制。然后，我们将使用质谱和其他生化技术研究 FCAS NLRP3 在这些细胞中的行为。最终，有关炎症小体和 NLRP3 的功能和调节的新知识可以帮助开发治疗炎症性疾病患者的新药。

项目成果

The Achromobacter type 3 secretion system drives pyroptosis and immunopathology via independent activation of NLRC4 and NLRP3 inflammasomes.

• DOI: 10.1016/j.celrep.2023.113012
• 发表时间: 2023-08-29
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Turton K;Parks HJ;Zarodkiewicz P;Hamad MA;Dwane R;Parau G;Ingram RJ;Coll RC;Bryant CE;Valvano MA
• 通讯作者: Valvano MA

Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS)

• DOI: 10.1136/thorax-2023-220292
• 发表时间: 2023-12-26
• 期刊: THORAX
• 影响因子: 10
• 作者: Mehta，Puja;Samanta，Romit J.;O'Kane，Cecilia M.
• 通讯作者: O'Kane，Cecilia M.