University of Dundee

MRC DTP 4 Year PhD Programme: Understanding the role of IL-33 in Type 2 driven immunity

This project is offered as part of the University of Dundee 4-year MRC DTP Programme “Quantitative and Interdisciplinary approaches to biomedical science”. This PhD programme brings together leading experts from the School of Life Sciences (SLS), the School of Medicine (SoM) and the School of Science and Engineering (SSE) to train the next generation of scientists at the forefront of international science.  The outstanding biomedical research at the University of Dundee was recognised by its very high rankings in REF 2014, with Dundee rated as the top University for Biological Sciences in the UK.  A wide range of projects are available within this programme crossing exceptional strengths in four key areas: Infection and Disease; Responses to Cellular Stresses; Development, Stem Cells and Neurobiology; and Big Data and Translation.  All students on this programme will receive training in computational biology, mathematical biology and statistics to equip with the quantitative skills in tackling complex biological questions.  In the 1st year, students will carry out 3 rotation projects prior to selection of the final PhD project.

Supervisors: Prof Simon Arthur and Dr Henry McSorley

IL-33 is an IL-1 related cytokine that helps promote Th2 type cytokine responses and has been strongly linked to asthma and atopic dermatitis. IL-33 mediates its effects in part by targeting mast cells and type 2 innate lymphoid cells(ILC2), both of which express high levels of the IL-33 receptor.Stimulation of both mast cells with IL-33 leads to the production of cytokines and chemokines (1) while in ILC2s IL-33 stimulates both cytokine production and cell proliferation. The molecular changes induced by IL-33 in these cells are not fully understood, and how the IL-33 induced response is modulated by other signals is unknown. Prostaglandin E (PGE2) is known to have a variety of immunomodulatory effects. For example, in macrophages, PGE2 represses the ability of the macrophage to produce pro-inflammatory cytokines but promotes its ability to produce the anti-inflammatory cytokine IL-10 (2).PGE2 is also able to stimulate mast cells and ILC2s, however mast cells express different PGE2 receptor subtypes compared to macrophages and the pathways by which PGE2 modulate IL-33 induced mast cell responses have not been established.Recent advances in mass spectrometry have established methods that allow the analysis of changes in protein expression and phosphorylation to be determined at a proteome level.This project will use a combination of phospho-and total proteomic studies to map the pathways activated following the stimulation of human iPS cell derived mast cells with IL-33 and prostaglandin E. Once key pathways are established their relevance in ILC2 will be examined. Finally, to establish their therapeutic potential, selected pathways blocked and the effects on an Alternaria induced asthma model will be examined.

Recent work from the lab can be found in the following references:

1: McCarthy PC, Phair IR, Greger C, Pardali K, McGuire VA, Clark AR, Gaestel M,Arthur JSC. (2019) IL-33 regulates cytokine production and neutrophil recruitment viathe p38 MAPK-activated kinases MK2/3. Immunol Cell Biol.97(1):54-71.

2: MacKenzie KF, Clark K, Naqvi S, McGuire VA, Nöehren G, Kristariyanto Y, vanden Bosch M, Mudaliar M, McCarthy PC, Pattison MJ, Pedrioli PG, Barton GJ, TothR, Prescott A, Arthur JS. (2013) PGE(2) induces macrophage IL-10 production and aregulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J Immunol.190(2):565-77

3: Arthur JS, Ley SC. (2013) Mitogen-activated protein kinases in innate immunity. NatRev Immunol. 13(9):679-92.