MCCIR AZ/GSK Update Seminar Series
| Dates: | 2 February 2015 |
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| Times: | 15:30 - 16:30 |
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| What is it: | Seminar |
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| Organiser: | Faculty of Life Sciences |
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| Who is it for: | University staff |
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| Speaker: | Lauren Cholewa, Alek Grabiec |
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Classical activation of macrophages induces STAT-dependent downregulation of the transcription factor FoxO3 - Alek Grabiec:
Forkhead box O (FoxO) transcription factors regulate expression of genes involved in responses to oxidative stress, proliferation and apoptosis. Recently FoxO proteins have emerged as important regulators of the immune system and reduced expression of FoxOs has been reported in inflammatory diseases, indicating that FoxO activity is required for an effective but self-limiting immune response, and that restoration of FoxO function might be beneficial in chronic inflammation. In this study we show that FoxO3a expression was rapidly reduced in human and mouse macrophages polarized towards an inflammatory M1 phenotype by interferon (IFN)? or granulocyte-macrophage colony-stimulating factor (GM-CSF). Downregulation of FoxO3a was indepen¬dent of PI3K-AKT signalling, but dependent on the JAK-STAT pathway: inhibition of JAK1/JAK2 activity fully restored FoxO3a expression in M1-polarized macrophages. Finally, macrophage FoxO3a expression profile was tissue specific: murine alveolar macrophages expressed significantly lower FoxO3a levels compared to macrophages from other tissues, and FoxO3a expression was further reduced in alveolar macrophages upon influenza infection. Collectively, these observations indicate that FoxO3a downregulation is strongly associated with inflammatory activation of macrophages and that pharmacological modulators of STAT activity could regulate FoxO3a function in inflammation.
Regulation of innate immunity in a novel model of pulmonary sarcoidosis - Lauren Cholewa:
Pulmonary sarcoidosis is characterised by non-caseating epithelioid granulomas with an influx of CD4+ T-lymphocytes. An increase in Th1 inflammatory mediators is observed including IFN-? and TNF-?, a main producer of which is alveolar macrophages. Increased production of matrix components such as hyaluronan and the acute phase inflammatory protein serum amyloid A is seen, the latter at higher levels than in any other pulmonary inflammatory condition. In a minority of cases chronic fibrotic disease occurs instead of self-resolution, which is not reflected in current models of the disease. As such we are developing a novel murine model using KatG, a mycobacterial antigen found in tissue samples of a subset of sarcoid patients, and serum amyloid A. The model will be used to examine the innate inflammatory tone of the airspaces, mechanisms leading to and increased infectious risk and therapeutic strategies to alleviate this condition. Although alveolar macrophages are thought to be involved in granuloma formation, their exact role in sarcoidosis is unclear. Using PCR, we have shown that the matrix component hyaluronan drives the up-regulation of the microRNAs let-7b and let-7c in airway macrophages. These miRNA species are known to impact on Toll-like receptor responsiveness and may explain the increased susceptibility to infections in patients with sarcoidosis.
Speakers
Lauren Cholewa
Role: PdD Student
Organisation: MCCIR
Alek Grabiec
Role: Research Associate
Organisation: MCCIR
Travel and Contact Information
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Michael Smith Lecture Theatre
Michael Smith Building
Manchester
