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    Investigating the expression and function of neutrophil elastase in murine monocyte migration in vivo 
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    • Investigating the expression and function of neutrophil elastase in murine monocyte migration in vivo
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    Investigating the expression and function of neutrophil elastase in murine monocyte migration in vivo

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    Leese_Andrew_PhD_Final_061115.pdf (5.813Mb)
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    Queen Mary University of London
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    Abstract
    Monocytes comprise a key component of the innate immune system. Their excessive and/or prolonged recruitment and/or activation can however be harmful and has been associated with the pathogenesis of numerous inflammatory disorders, most notably atherosclerosis. Consequently there is much interest in deciphering the mechanisms by which monocytes migrate into sites of inflammation. In this context, whilst many studies have investigated the roles of adhesion molecules and chemokine receptors, very little attention has been placed on the potential involvement of proteases. To help address this point, and considering cigarette smoke-induced recruitment of monocytes to the lung is impaired in mice deficient in neutrophil elastase (NE-/-), we sought to further investigate the role of NE, a serine protease, in monocyte migration. To achieve this we successfully crossed CX3CR1-eGFP-knock-in mice, which exhibit fluorescently labelled monocytes, with NE-/- mice. By comparing NE-/- and NE+/+ littermates we demonstrated, for the first time, NE expression in murine monocytes. Peritonitis, ear, and cremaster muscle models of inflammation were subsequently employed to assess the involvement of NE in monocyte recruitment. In CCL2-induced peritonitis, a predominantly monocyte-driven inflammatory model, monocyte infiltration was significantly reduced after 16 hours in NE-/- mice compared to NE+/+ controls. Monocyte transmigration was also defective in the ears (though interestingly not the cremaster muscles) of NE-/- mice stimulated with CCL2, with the majority of monocytes seemingly unable to penetrate the venular endothelium. Furthermore, immunostaining revealed transmigrating monocytes were depleted of their intracellular NE stores. Taken together, it appears the release of NE by monocytes promotes their transmigration in response to CCL2, identifying NE as a potential therapeutic target for monocyte-driven pathologies.
    Authors
    Leese, Andrew John
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    http://qmro.qmul.ac.uk/xmlui/handle/123456789/12853
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    The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author
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