Experimental Inflammation

Mechanisms that control the resolution of inflammation are largely understudied. We hypothesise that inherent (genetic) or acquired defect in pro-resolution pathways, such as age or pathogenic infections, contribute to the development of chronic inflammation. This, therefore, represents a unique opportunity to discover novel endogenous biochemical pathways that switch off inflammation and that may be harnessed for therapeutic gain with fewer side effects.

Expertise in human experimental medicine, including: 

• Infectious - dermal E. coli, S pneumoniae
• Nonspecific / Tissue Injury - dermal cantharidin
• Adaptive - dermal PTP or VZV antigen
• Systemic - i.v. endotoxin
• Wound healing

Reverse translation of key findings in humans to matched rodent models.

1. We are curious about the impact of processes that are activated following the resolution of acute inflammation; specifically, how they help to imprint long term tissue immunity. By this, we refer to a sequence of events following resolving inflammation that enhances immune barrier function driven, in part, by prostanoids and that also limits tissue injury/fibrosis.
2. Lipid mediators and immune cell maturation. We are currently investigating how lipid mediators derived from linoleic acid and other PUFAs mature sub-populations of granulocytes and mononuclear phagocytes for roles in resolving inflammation; we see this is a hitherto unappreciated facet of pro-resolution biology.
3. Identification of novel pro-resolution pathways and intracellular signalling complexes with macrophages that drive resolution in humans.

We are interested in the pathways that resolve inflammation, hypothesising that their dysregulation drives chronic inflammatory diseases.

I was the first to show that lipids resolve inflammation (Nature Medicine 1999; J. Exp. Med 2004; PNAS, 2007; PNAS 2010). These reports highlighted that some classes of anti-inflammatory drugs, paradoxically, prolong inflammation. These controversial findings were supported by data showing pro-resolution property of NFkappaB leading to "negative immune signalling" converging on inflammatory resolution (Nature Medicine, 2001).

This research has formed the basis for our current hypothesis that pro-resolution biochemical pathways shape long term tissue immunity mediated by myeloid cells (Blood 2014) synthesising lipid mediators (Cell Reports, 2017); the phenotype and trafficking of these myeloid cells is controlled by oxylipins derived from cytochrome p450, PNAS 2016.

Case Example 1: We developed experimental models of inflammation in humans (PNAS 2010, PLoS One 2014, 2016 & 2017; J Pathol. Clin. Res., 2016; J Exp Med 2017; Clin Pharm. Therapeutics 2018). Using one of these models, we discovered the molecular basis of a resolution defect in old people and, using a clinical grade pharmacological inhibitor, transiently rejuvenated their immune system to that of a younger person (Nature Immunology 2020). 

Case Example 2: We applied basic science to understand cirrhosis patient’s susceptibility to infection (Nature Medicine 2014). With Funding from the Wellcome Trust Heath Innovation Challenge Fund we demonstrated that albumin – believed to be anti-inflammatory and administered liberally to cirrhosis patients – had no benefit in preventing death in these patients. This questioned the use of this expensive drug in this setting (New England Journal of Medicine 2021).

Therefore, my laboratory has advanced the understanding of resolution biology and novel resolution defects in humans while developing human models to take observations from mice-to-man and back again, in a reverse-translational manner.