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，可保护我们免受入侵微生物的影响。例如，当我们割伤手指时，我们认为实际上有助于我们清除感染并治愈伤口的发红，热量和疼痛。因此，炎症通常对我们有益。但是，很明显，炎症在许多疾病中也起着负面作用，尤其是与衰老和代谢相关的疾病。在关节炎，肝病和阿尔茨海默氏病等疾病中，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，因为这可以为我们对这些普遍疾病的理解提供了理解，这对我们的健康服务和社会造成了巨大负担。我们的研究建议的主要目的是发现在免疫反应期间如何调节或微调称为炎症体的蛋白质复合物。炎性体，特别是一种称为NLRP3的炎性体，是我们免疫细胞中炎症最有效的原因之一。我们的初步实验表明，与发烧过程中发生的温度相似，似乎特异性地阻止了炎症引起的炎症。这表明免疫反应已开发出一种限制这些炎症造成的过度或有害炎症的方法。我们想了解这是如何发生的，我们的研究的第一个目的是定义热休克蛋白（HSP）如何自然诱发高温会影响炎症体活动。为此，我们将使用称为巨噬细胞的免疫细胞进行实验，这些免疫细胞表达高水平的炎性蛋白。我们将使用HSP的化学抑制剂研究HSP功能如何影响炎症体依赖性炎症和炎性蛋白的相互作用。我们的下一个重点将是炎症体传感器蛋白NLRP3。我们已经开发了一个新想法，即NLRP3本身可以感觉到温度的变化。温度的变化是所有生物都面临的生理压力，并且由于NLRP3能够感觉到许多类型的细胞应激，因此也可能是热传感器。为了研究这个想法，我们将使用先进的技术（例如定量质谱法）来确定NLRP3在加热到发烧范围温度时的表现。我们怀疑NLRP3如何与其他蛋白质相互作用会随温度变化而变化。我们的第三个目标是了解如何通过冷温激活NLRP3的突变形式。 NLRP3中的突变引起了一种罕见的遗传疾病，称为家族性冷自身炎症综合征（FCAS）。 FCAS患者在暴露于寒冷温度时会出现炎症症状，例如皮疹和发烧。还没有人知道这种异常反应是如何发生的，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。在本文中，有关炎症和NLRP3功能和调节的新知识可以帮助为患有炎症性疾病患者的新药开发新药物。

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.