Abstract
Most of the ageing-associated pathologies are coupled with a strong inflammatory component that accelerates the progress of the physiopathological functional decline related to ageing. The currently available pharmacological tools for the control of neuroinflammation present several side effects that restrict their application, particularly in chronic disorders. The discovery of the potential anti-inflammatory action exerted by endogenous oestrogens, as well as the finding that activation of oestrogen receptor α results in a significant decrease of inflammation at the cellular level and in models of inflammatory diseases, prompted us to embark in a series of studies aimed at the generation of reporter systems, allowing us to (i) understand the anti-inflammatory action of oestrogens at molecular level; (ii) evaluate the extent to which the action of this steroid hormone was relevant in models of pathologies characterised by a strong inflammatory component; and (iii) investigate the efficacy of novel, synthetic oestrogens endowed with anti-inflammatory activity. Accordingly, we conceived the NFκB-luc2 reporter mouse, a model characterised by dual reporter genes for fluorescence and bioluminescence imaging under the control of a synthetic DNA able to bind the transcription factor nuclear factor kappa B, the master regulator of the expression of most of the cytokines responsible for the initial phase of acute inflammation. Here, we summarise the philosophy that has driven our research in the past years, as well as some of the results obtained so far.
Highlights
Results in a significant decrease of inflammation at the cellular level and in models of inflammatory diseases, prompted us to embark in a series of studies aimed at the generation of reporter systems allowing to i.) understand the anti-inflammatory action of estrogens at molecular level, ii.) evaluate the extent to which the action of this steroid hormone was relevant in models of pathologies characterized by a strong inflammatory component and iii.) investigate the efficacy of novel, synthetic estrogens endowed of anti-inflammatory activity
Most pathologies associated with ageing and the ageing process itself are characterized by a strong inflammatory component that accelerates the progress of the physiological, or pathology-induced functional decline related to ageing
The discovery that endogenous estrogens have anti-inflammatory potential and that activation of ERα and ERβ results in a significant decrease of inflammation at the cellular level and in models of inflammatory diseases [6,7,8,9,10,11,12,13,14] led us to initiate a series of studies aimed at the generation of model systems where we could i.) understand the anti-inflammatory action of estrogens at the molecular level, ii.) evaluate the extent to which the action of this steroid hormone was relevant in models of pathologies characterized by a strong inflammatory component and iii.) study the efficacy of novel, synthetic estrogens endowed of with anti-inflammatory activity
Summary
Most pathologies associated with ageing and the ageing process itself are characterized by a strong inflammatory component that accelerates the progress of the physiological, or pathology-induced functional decline related to ageing. These limitations are evident for fluorescence imaging, and this is partially circumvented using emitters in the red region of the spectrum The availability of these proteins, associated with the technology to integrate exogenous DNA into the genome of single cells and whole animals, permitted the creation/conception of model systems where the synthesis of the reporter protein occurred only in the presence of selected stimuli. For the promoter we utilized a DNA sequence able to bind the TF NFκB, the master regulator of the expression of most of the cytokines responsible for the initial phase of acute inflammation [24, 25, 26] Such promoter was completely synthetic and was the resultant of a thorough analysis of a panel of genes involved in innate immunity which led us to identify two major groups of NFκB consensus sequences. Even the in vivo analysis of LPS activity indicated that estrogens can limit in time the inflammatory response
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