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

肿瘤坏死因子α (TNF)是先天免疫反应的主要介质。它被描述为炎症的“守门人”，参与多种细胞反应，包括白细胞的激活和募集、粘附分子表达的上调、上皮和内皮屏障通透性的控制、细胞凋亡/坏死的诱导、离子通道表达的调节等。因此，TNF在炎症反应的诱导和随后的解决中都是一个至关重要的角色，尽管它已经研究了很多年，但我们对其复杂生物学的了解仍然存在很大的差距。通过之前与GSK的合作研究，我们已经使用特异性药物阻断（p55靶向结构域抗体）开始研究体内TNF受体功能的特异性机制，由于基因操作的慢性代偿效应，这些机制在突变小鼠中难以探索。从这些研究中可以清楚地看出，尽管急性肺内p55抑制降低了肺内白细胞浸润和肺液平衡，但这两个过程并不一定相关，即在不同的情况下，p55抑制可能减弱其中一个过程而不影响另一个过程。有证据还表明，急性阻断p55仅具有短暂的延迟炎症期间白细胞募集和屏障通透性的能力(4)。虽然这可以简单地解释为体内使用的抗体生物活性的丧失，但也有可能抑制这种重要途径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，但仍然非常需要进一步了解p55信号传导的机制和结果。我们对细胞内p75信号的理解正在改善，但仍落后于p55(5)。我们已经证明p75基因敲除小鼠的急性肺部炎症和损伤大大加剧，但仍不清楚其机制。为了开始纠正这种情况，我们最近与GSK合作，使用rna测序技术来鉴定表达受p55或p75调控的基因。通过之前与GSK的合作研究，我们已经使用特异性药物阻断（p55靶向结构域抗体）开始研究体内TNF受体功能的特异性机制，由于基因操作的慢性代偿效应，这些机制在突变小鼠中难以探索。从这些研究中可以清楚地看出，尽管急性肺内p55抑制降低了肺内白细胞浸润和肺液平衡，但这两个过程并不一定相关，即在不同的情况下，p55抑制可能减弱其中一个过程而不影响另一个过程。证据还表明，急性阻断p55仅具有短暂的延迟炎症期间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生物活性的丧失，但也有可能抑制这种重要途径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，但仍然非常需要进一步了解p55信号传导的机制和结果。我们对细胞内p75信号的理解正在改善，但仍落后于p55。我们已经证明p75基因敲除小鼠的急性肺部炎症和损伤大大加剧，但仍不清楚其机制。为了开始纠正这种情况，我们最近与GSK合作，使用rna测序技术来鉴定表达受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.