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

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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.