TNF- alpha Receptor Signalling in the Regulation and Resolution of Acute Inflammation

肿瘤坏死因子是先天免疫反应的主要介体。它被认为是炎症的守门人，参与多种细胞反应，包括白细胞的激活和募集、黏附分子表达的上调、上皮和内皮屏障通透性的控制、诱导细胞凋亡/坏死下垂、离子通道表达的调节等。因此，肿瘤坏死因子在炎症反应的诱导和随后的消退过程中都起着至关重要的作用，尽管人们已经对其进行了多年的研究，但我们对其复杂的生物学特性的了解仍然存在很大的空白。通过与葛兰素史克之前的合作研究，我们已经开始使用特定的药物阻断(P55靶向结构域抗体)来研究体内肿瘤坏死因子受体功能的特定机制，由于基因操作的慢性代偿效应，这些机制在突变小鼠中很难探索。从这些研究中明确的一件事是，虽然急性肺内抑制P55减少了白细胞对肺的渗透和肺液平衡，但这两个过程并不一定是联系在一起的，即在不同的情况下，抑制P55可能会减弱这两个过程中的任何一个，而不影响另一个过程。证据还表明，急性阻断P55只能短暂地延缓炎症期间的白细胞募集和屏障通透性(4)。虽然这可以简单地解释为体内使用的抗体失去生物活性，但抑制这一重要途径也可能对炎症的消退产生不利影响。因此，虽然我们的知识有所增加，但仍有必要进一步了解体内p55信号转导的机制和后果。我们对细胞内p75信号的理解正在提高，但仍然落后于p55(5)。我们已经证明，在p75基因敲除的小鼠中，急性肺部炎症和损伤大大加剧，但机制仍不清楚。为了开始纠正这种情况，我们最近与葛兰素史克联合使用了RNA测序技术来识别其表达受p55或p75调控的基因。通过之前与葛兰素史克的合作研究，我们已经使用特定的药物阻断(P55靶向结构域抗体)来开始研究体内肿瘤坏死因子受体功能的特定机制，这些机制由于基因操作的慢性代偿效应而在突变小鼠中很难探索。从这些研究中明确的一件事是，虽然急性肺内抑制P55减少了白细胞对肺的渗透和肺液平衡，但这两个过程并不一定是联系在一起的，即在不同的情况下，抑制P55可能会减弱这两个过程中的任何一个，而不影响另一个过程。证据还表明，在炎症过程中，急性阻断P55只有短暂的延缓白细胞募集和屏障通透性的能力。虽然这可以简单地解释为体内使用的抗体失去生物活性，但抑制这一重要途径也可能对炎症的消退产生不利影响。因此，虽然我们的知识有所增加，但仍有必要进一步了解体内p55信号转导的机制和后果。我们对细胞内p75信号的理解正在提高，但仍然落后于p55。我们已经证明，在p75基因敲除的小鼠中，急性肺部炎症和损伤大大加剧，但机制仍不清楚。为了开始纠正这种情况，我们最近与葛兰素史克联合使用了RNA测序技术来识别其表达受p55或p75调控的基因。

Tumour necrosis factor alpha (TNF) is a major mediator of the innate immune response. It has been described as a 'gate-keeper' of inflammation, and is involved in wide variety of cellular responses, including activation and recruitment of leukocytes, upregulation of adhesion molecule expression, control of epithelial and endothelial barrier permeability, induction of cellular apoptosis/necroptosis, regulation of ion channel expression and a host of others. TNF is therefore a vital player in both the induction and subsequent resolution of the inflammatory response, and although it has been researched for many years there are still substantial gaps in our knowledge of its' complicated biology.Through previous collaborative studies with GSK, we have used specific pharmacological blockade (p55-targeting domain antibodies) to start to investigate specific mechanisms of in vivo TNF receptor function, which are difficult to explore in mutant mice due to chronic compensatory effects of gene manipulation. One thing that has become clear from these studies is that while acute intra-pulmonary inhibition of p55 reduces both leukocyte infiltration into the lungs and lung fluid balance, these two processes are not necessarily linked, i.e. under different circumstances p55 inhibition may attenuate either of these processes without influencing the other. The evidence also suggests that acute blockade of p55 has only a transient ability to delay leukocyte recruitment and barrier permeability during inflammation (4). While this could simply be explained by loss of biological activity of the antibodies used in vivo, it is also possible that inhibition of such an important pathway may adversely impact on resolution of inflammation. Therefore, while our knowledge has increased, there is still a great need for further understanding of the mechanisms and consequences of p55 signalling in vivo. Our understanding of intracellular p75 signalling is improving, but remains behind that of p55 (5). We have shown that acute pulmonary inflammation and injury is greatly exacerbated in p75 knockout mice, but remain in the dark regarding mechanisms. To start to rectify this situation we have recently, in conjunction with GSK, used RNA-sequencing technology to identify genes whose expression is regulated by either p55 or p75. Through previous collaborative studies with GSK, we have used specific pharmacological blockade (p55-targeting domain antibodies) to start to investigate specific mechanisms of in vivo TNF receptor function, which are difficult to explore in mutant mice due to chronic compensatory effects of gene manipulation. One thing that has become clear from these studies is that while acute intra-pulmonary inhibition of p55 reduces both leukocyte infiltration into the lungs and lung fluid balance, these two processes are not necessarily linked, i.e. under different circumstances p55 inhibition may attenuate either of these processes without influencing the other. The evidence also suggests that acute blockade of p55 has only a transient ability to delay leukocyte recruitment and barrier permeability during inflammation. While this could simply be explained by loss of biological activity of the antibodies used in vivo, it is also possible that inhibition of such an important pathway may adversely impact on resolution of inflammation. Therefore, while our knowledge has increased, there is still a great need for further understanding of the mechanisms and consequences of p55 signalling in vivo. Our understanding of intracellular p75 signalling is improving, but remains behind that of p55. We have shown that acute pulmonary inflammation and injury is greatly exacerbated in p75 knockout mice, but remain in the dark regarding mechanisms. To start to rectify this situation we have recently, in conjunction with GSK, used RNA-sequencing technology to identify genes whose expression is regulated by either p55 or p75.