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，是我们免疫反应的重要组成部分，它保护我们免受入侵微生物的侵害。例如，当我们的手指割伤时，我们感受到的红肿、热和疼痛实际上帮助我们清除感染并治愈伤口。因此，炎症通常对我们是有益的。然而，越来越清楚的是，炎症在许多疾病中也起着负面作用，尤其是那些与衰老和新陈代谢有关的疾病。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，我们必须研究炎症的分子机制，因为这有助于我们了解这些对我们的卫生服务和社会造成巨大负担的流行疾病。我们的研究计划的主要目的是发现一种叫做炎性体的蛋白质复合物是如何在免疫反应中被调节或微调的。炎性小体，特别是一种叫做NLRP3的炎性小体，是我们免疫细胞炎症的最有效原因之一。我们的初步实验表明，温度升高，类似于发烧时的温度升高，似乎可以特异性地阻止炎症小体引起的炎症。这表明免疫反应已经发展出一种方法来限制这些炎性小体引发的过度或有害的炎症。我们想了解这是如何发生的，我们研究的第一个目标是确定高温自然诱导的热休克蛋白（HSPs）如何影响炎性体的活性。为此，我们将使用免疫细胞巨噬细胞进行实验，巨噬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性小体依赖性炎症和炎性小体蛋白的相互作用。我们的下一个重点将是炎性体传感器蛋白NLRP3。我们有了一个新的想法，NLRP3本身可以感知温度的变化。温度的变化是所有生物都面临的生理压力，由于NLRP3能够感知多种类型的细胞压力，因此它也可以是一个热传感器。为了研究这一想法，我们将使用定量质谱等先进技术来确定NLRP3在细胞被加热到发烧范围温度时的行为。我们怀疑NLRP3与其他蛋白质的相互作用会随着温度的变化而改变。我们的第三个目标是了解NLRP3的突变形式是如何被低温激活的。NLRP3突变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患者暴露在低温环境中时，会出现皮疹和发烧等炎症症状。没有人知道这种不寻常的反应是如何发生的，所以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，关于炎性小体和NLRP3的功能和调控的新知识可以帮助开发治疗炎症性疾病的新药。

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.