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Redefining the role of tumour necrosis factor in macrophage differentiation and effector function in bacterial and tumour defences

thesis
posted on 2023-05-27, 09:06 authored by Li, X
Tumour necrosis factor ˜í¬± (TNF) is an essential pro-inflammatory cytokine predominantly secreted by macrophages that regulates the inflammatory response to infection. Macrophages are essential phagocytic innate immune cells resident in all tissues. In response to distinct stimuli, macrophages are polarized into classically activated macrophages (CAM) or alternatively activated macrophages (AAM). CAM have a pro-inflammatory phenotype with a strong ability in killing invading pathogens whereas AAM display an anti-inflammatory phenotype and promote tissue repair. The enzymes iNOS and Arginase-1 are signature molecules expressed by CAM and AAM, respectively, and they use the same substrate L- arginine competitively. TNF plays a central role in restricting AAM differentiation in parasitic infection with Leishmania (L.) major and a tumour model and we hypothesized that it would be applicable generally. Therefore, this thesis investigated the role of TNF in the activation of macrophages during an infection with the gram-positive bacterium Listeria (L.) monocytogenes. Wild-type and B6.TNF\\(^{-/-}\\) mice were infected with L. monocytogenes and macrophage differentiation in spleen (Chapter 3) and peritoneum (Chapter 4) was analysed. TNF deficiency resulted in high susceptibility of infected mice to L. monocytogenes with high bacterial loads in spleen and liver. In addition, there was a strong expression of Arginase-1 and an intact presence of iNOS in splenic and peritoneal macrophages, indicating a regulation of AAM differentiation during L. monocytogenes infection by TNF. Furthermore, in response to the alternative activation of macrophages in B6.TNF\\(^{-/-}\\) mice, the number of splenic neutrophils and the titre of the pro-inflammatory cytokine IL-1˜í‚⧠increased. This indicates that TNF also orchestrates immune responses to bacterial infection and indicates that its role in the suppression of central molecules of the AAM signature such as Arg1 is a general phenomenon. In addition, this thesis investigated the role of TNF in phagocytosis of L. monocytogenes and Devil Facial Tumour Disease (DFTD) cells by macrophages (Chapter 5). We examined macrophage phagocytosis of L. monocytogenes and DFTD cells by macrophages from wild- type and B6.TNF-/- mice. Under steady state conditions there was no difference in phagocytosis efficiency. However, the treatment of macrophages with IFN˜í‚â• plus LPS or LPS alone increased phagocytosis in macrophages from B6.TNF\\(^{-/-}\\) mice, to a greater degree than macrophages from wild type mice. It is likely that TNF regulates phagocytosis of DFTD cells by activated macrophages. In summary, these results indicate a key role for TNF in orchestrating innate immune responses through modulating the macrophage differentiation and phagocytosis. The AAM bias in the absence of TNF leads to the high susceptibility to bacterial infection, suggesting an essential effect of TNF in an anti-bacterial response.

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