The complement system and inflammation
The complement system is a very important part of the innate immune system that helps us to combat invading pathogens. Activation of the complement cascade is a tightly regulated and well-maintained process, however when dysregulated it has been implicated in a number of inflammatory and autoimmune disorders. The research in our lab focuses predominantly on the C5a and C3a complement proteins, both key inflammatory mediators. C3a binds to C3aR and C5a binds to either C5a1 and C5a2.
These receptors we are researching belong to a particular class of receptors involved in inflammation called GPCRs, or G protein coupled receptors. GPCRs account for up 30% of the targets of drugs currently on the market and are of interest to Big pharma, academia and biotech. They are commonly referred to as 7TM proteins as they are composed of seven helices that span the membrane. They are implicated in many disease types, due to their widespread expression in a number of different cell types, particularly immune cells. We are interested in GPCRs and the pathology of native and synthetic ligands for these receptors that play a central role in host defense . Excessive complement receptor activation and dysregulation has been linked to a number of different disease types, including rheumatoid arthritis , sepsis  and Alzheimer’s . Whilst much effort (20 years+) has been put into the development of potent antagonists against this receptor, there are no marketed antagonists to date.
Our group has attempted to understand the complex relationship between the two different GPCRs of C5a, demonstrating that C5a2 is not just a ‘dud’ receptor, as previously believed. Our findings have given us a foundation to pursue novel therapeutics that specifically act via C5a2 and not C5a1.
- Klos, A., Wende, E., Wareham, K.J., and Monk, P. N. International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors. Pharmacol Rev (2013), 65, 500-543
- Croker, D. E., R. Halai, G. Kaeslin, E. Wende, B. Fehlhaber, A. Klos, P. Monk and M. A. Cooper. C5a2 can modulate ERK1/2 signaling in macrophages via heteromer formation with C5a1 and β-arrestin recruitment.. (2014) Immunol Cell Biol, 92, 631-639
- Schofield, Z.V, Woodruff, T.M., Halai, R., Wu, M.C.L., Cooper, M. A. Neutrophils-a key component of ischemic reperfusion injury.(2013), Shock, 40, 463-70
- Croker, D. E., Halai R., Fairlie, D. P., Cooper M.A. C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5aR and C5L2. (2013) Immunol Cell Biol, 91, 625-633
- Wu, M.C.L, Brennan, F.H, Lynch, J.P., Mantovani, S., Phipps, S., Wetsel, R.A., Ruitenberg, M.J., Taylor, S.M., Woodruff, T.M. The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization (2013) PNAS, 110, 9439-9444
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Intestinal reperfusion injury and inflammation
Inflammation is the body’s response to injury and or infection and provides a necessary function for protection and repair. Inflammation is typically considered a mechanism of innate immunity which is a closely regulated system. However, in rare cases, such as trauma and severe infection, acute inflammation can become aberrant causing ischemia reperfusion injury (IRI).
IRI is a common, damaging and untreatable event that can lead to multiple organ failure (MOF) and death (1). The excessive injury seen in IRI is caused by an exacerbated inflammatory response mediated by neutrophils (2). Current therapeutic options provide palliative care at best, with significant un-met medical need. Thus it is still a research imperative to investigate the mechanisms and find treatments to prevent IRI.
Our group is investigating the role of the innate immune system with a particular interest for neutrophils and the G protein coupled receptor (GPCR) free fatty acid receptor 2 (FFA2). FFA2, the endogenous ligand for short chain fatty acids(3), is highly expressed on neutrophils. Our twofold approach is exploring the innate mechanisms of IRI in vivo and ex vivo using wild type and knockout models as well as primary cells. Whereas our in vitro work is receptor focused and aims to reveal discreet signalling pathways using FRET, BRET, FLIPR and label free technologies for the purpose of designing optimum therapeutics.
1. Widgerow AD: Ischemia-Reperfusion Injury: Influencing the Microcirculatory and Cellular Environment. Annals of plastic surgery 00(00): 1–8, 2012 Dec 13.
2. Schofield ZV, Woodruff TM, Halai R, Wu MC-L, Cooper MA: Neutrophils-a key component of ischemia-reperfusion injury. Shock (Augusta, Ga) 40(6): 463–70, 2013 Dec.
3. Le Poul E, Loison C, Struyf S, Springael J-Y, Lannoy V, Decobecq M-E, et al.: Functional characterization of human receptors for short chain fatty acids and their role in polymorphonuclear cell activation. The Journal of biological chemistry 278(28): 25481–9, 2003 Jul 11.