University of Dundee

Dr Simon Arthur

Signaling networks that control inflammation
Position: 
Reader and Deputy Head of the Division of Cell Signalling and Immunology
Address: 
School of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH
Full Telephone: 
+44 (0) 1382 384003, int ext 84003
Email: 

Research

The body's immune system is essential for defense against infection and wound healing. However excessive, or inappropriate, activation of the immune system results in unwanted damage to healthy tissue. Infection or injury is detected by immune cells, which then trigger a complex inflammatory reaction designed to clear the pathogen and/or promote tissue repair. Normally this is then followed by a resolution phase during which inflammation decreases and the immune system is deactivated. Excessive inflammation however can cause tissue damage or cytokine storms. In severe cases this can result in septic shock, a condition that still has limited treatment options and high mortality. A failure of resolution results in chronic inflammation, a condition that underlies the pathology of autoimmune and auto-inflammatory conditions. These diseases, which include rheumatoid arthritis, psoriasis, lupus and vasculitis, represent a major health problem, and together can affect 3-4% of the population in Western society. Autoimmune disorders are often serious and can lead to significant disability and in some cases mortality. While modern drug treatments can be effective in providing relief from these conditions, they do not provide a cure and can themselves result in significant adverse side effects. Thus more research is needed to provide a full understanding of the causes and pathology of these conditions to enable improved therapies to be developed. Inflammation is a complex multistage process involving multiple cell types from both the innate and adaptive immune systems and is tightly coordinated by a range of pro-inflammatory cytokines and chemokines. Further control is also achieved via the induction of anti-inflammatory cytokines that act to keep inflammation within acceptable limits and to promote the resolution of inflammation.

We are primarily interested in the roles that cells of the innate immune system play in coordinating inflammation and how they contribute to activation of adaptive immunity via the production of cytokines. Innate immune cells are able to recognize specific components of pathogens – referred to as pathogen associated molecular patterns or PAMPs. Several groups of receptors for PAMPs have been described, including Toll like receptors, C-type lectins and NOD-like proteins. These receptors trigger the activation of several intracellular signaling pathways, including the mitogen activated protein kinase (MAPK), NFkappaB and TBK1/IRF systems leading to the transcription and production of both pro- and anti-inflammatory cytokines. Our main focus is to understand the roles these intracellular signaling cascades play in both the initial inflammatory response and in the ability of innate immune cells, particularly macrophages and dendritic cells, to activate the adaptive immune system. Finally we are interested in the ways in which intracellular signaling in innate immune cells controls the induction of anti-inflammatory and pro-resolution factors in order to deactivate the immune system.

Teaching

BS31006 - Genetics

BS32006 - Cell Signalling

BS32009 - Immunology

BS42006 - Advanced Immunology

BS42013 - Advanced Cell Signalling

Publications

McGuire, V. A., Rosner, D., Ananieva, O., Ross, E. A., Elcombe, S. E., Naqvi, S., van den Bosch, M. M., Monk, C. E., Ruiz-Zorrilla Diez, T., Clark, A. R. and Arthur, J. S. (2017) Beta Interferon Production Is Regulated by p38 Mitogen-Activated Protein Kinase in Macrophages via both MSK1/2- and Tristetraprolin-Dependent Pathways. Molecular and cellular biology. 37d.o.i 10.1128/MCB.00454-16
Pubmed: 5192081
PMC: 27795299

McGuire, V. A., Ruiz-Zorrilla Diez, T., Emmerich, C. H., Strickson, S., Ritorto, M. S., Sutavani, R. V., Weibeta, A., Houslay, K. F., Knebel, A., Meakin, P. J., Phair, I. R., Ashford, M. L., Trost, M. and Arthur, J. S. (2016) Dimethyl fumarate blocks pro-inflammatory cytokine production via inhibition of TLR induced M1 and K63 ubiquitin chain formation. Scientific reports. 6, 31159
d.o.i 10.1038/srep31159
Pubmed: 4976367
PMC: 27498693

Zhou, Z., Tang, A. T., Wong, W. Y., Bamezai, S., Goddard, L. M., Shenkar, R., Zhou, S., Yang, J., Wright, A. C., Foley, M., Arthur, J. S., Whitehead, K. J., Awad, I. A., Li, D. Y., Zheng, X. and Kahn, M. L. (2016) Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 532, 122-126
d.o.i 10.1038/nature17178
Pubmed: 4864035
PMC: 27027284

Tan, L., Akahane, K., McNally, R., Reyskens, K. M., Ficarro, S. B., Liu, S., Herter-Sprie, G. S., Koyama, S., Pattison, M. J., Labella, K., Johannessen, L., Akbay, E. A., Wong, K. K., Frank, D. A., Marto, J. A., Look, T. A., Arthur, J. S., Eck, M. J. and Gray, N. S. (2015) Development of Selective Covalent Janus Kinase 3 Inhibitors. Journal of medicinal chemistry. 58, 6589-6606
d.o.i 10.1021/acs.jmedchem.5b00710
Pubmed: 4777322
PMC: 26258521

Naqvi, S., Martin, K. J. and Arthur, J. S. (2014) CREB phosphorylation at Ser133 regulates transcription via distinct mechanisms downstream of cAMP and MAPK signalling. The Biochemical journal. 458, 469-479
d.o.i 10.1042/BJ20131115
PMC: 24438093

McGuire, V. A., Gray, A., Monk, C. E., Santos, S. G., Lee, K., Aubareda, A., Crowe, J., Ronkina, N., Schwermann, J., Batty, I. H., Leslie, N. R., Dean, J. L. E., O'Keefe, S. J., Boothby, M., Gaestel, M. and Arthur, J. S. C. (2013) Cross Talk between the Akt and p38α Pathways in Macrophages Downstream of Toll-Like Receptor Signaling. Molecular and Cellular Biology. 33, 4152-4165
d.o.i 10.1128/mcb.01691-12

Arthur, J. S. and Ley, S. C. (2013) Mitogen-activated protein kinases in innate immunity. Nature reviews. Immunology. 13, 679-692
d.o.i 10.1038/nri3495
PMC: 23954936

Venigalla, R. K., McGuire, V. A., Clarke, R., Patterson-Kane, J. C., Najafov, A., Toth, R., McCarthy, P. C., Simeons, F., Stojanovski, L. and Arthur, J. S. (2013) PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development. The EMBO journal. 32, 1008-1022
d.o.i 10.1038/emboj.2013.40
Pubmed: 3616287
PMC: 23463102

MacKenzie, K. F., Van Den Bosch, M. W., Naqvi, S., Elcombe, S. E., McGuire, V. A., Reith, A. D., Blackshear, P. J., Dean, J. L. and Arthur, J. S. (2013) MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop. Molecular and cellular biology. 33, 1456-1467
d.o.i 10.1128/MCB.01690-12
Pubmed: 3624268
PMC: 23382072

MacKenzie, K. F., Clark, K., Naqvi, S., McGuire, V. A., Noehren, G., Kristariyanto, Y., van den Bosch, M., Mudaliar, M., McCarthy, P. C., Pattison, M. J., Pedrioli, P. G., Barton, G. J., Toth, R., Prescott, A. and Arthur, J. S. (2013) PGE(2) induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. Journal of immunology. 190, 565-577
d.o.i 10.4049/jimmunol.1202462
Pubmed: 3620524
PMC: 23241891