Experimental Inflammation

Our philosophy

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.

Experimental models

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.

Ongoing projects

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.

Key achievements

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.

Facilities

We established a newly refurbished Clinical Research Facility which includes:

• Laser Doppler for scanning sites of local experimentally induced inflammation as a quantitative marker of vascular hyper reactivity
• two beds
• four negative pressure pumps for the purpose of eliciting skin blisters
• approved drugs cabinet
• heart/blood pressure monitor
• a TV system to occupy volunteers during procedures.

In addition to blistering as a means of acquiring immune cells for analysis by polychromatic flow cytometer (Spectral Flow), RNAseq etc, there is expertise in skin biopsies that maybe subjected to a wide array of analytic techniques including spatial transcriptomics, multiplex imaging etc.

The Gilroy Lab

Collaborators

• Professor Arne Akbar (UCL)
• Dr Marko Nikolic (UCL)
• Dr Darryl Zeldin (NIH, USA)
• Dr Daniel Gomez/Luciana Covre (Brazil)
• Professor Anna Nicolaou (Manchester University)

Publications

1. Feehan K, Bridgewater H, Stenkiewicz-Witeska J … Gilroy DW (In press, 2023). Post-resolution macrophage-derived lipids shapes long-term tissue immunity and integrity. Nature Communications.
2. Lanna A, Vaz B, D'Ambra C, Vuotto C ... Gilroy DW, et al (2022). An intercellular transfer of telomeres rescues T cells from senescence and promotes long-term immunological memory. Nature Cell Biology, 24(10): 1461–1474.
3. George MJ, Jasmin NH, Cummings VT ... Gilroy DW (2021). Selective Interleukin-6 Trans-Signaling Blockade Is More Effective Than Panantagonism in Reperfused Myocardial Infarction. JACC Basic Transl Sci. 6(5):431-443.
4. Pereira B, De Maeyer R, Covre L, Nehar-Belaid D ... Gilroy DW, et al (2020). Sestrins Induce Natural Killer Function In Senescent-like CD8+ T Cells. Nature Immunol 21(6):684-694.
5. China L, Freemantle N ... Gilroy DW, O'Brien A for the ATTIRE Trial Investigators (2021). A randomized clinical trial of albumin infusions to improve outcome in hospitalized cirrhosis patients. New England Journal of Medicine. 384(9):808-817.
6. De Maeyer RPH, van de Merwe RC ... Gilroy, DW (2020). Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat Immunol 21, 615–625.
7. Motwani MP, Colas RA, George MJ, Flint JD ... Gilroy DW (2018). Pro-resolving mediators promote resolution in a human skin model of UV-killed Escherichia coli-driven acute inflammation. JCI Insight. 2018 Mar 22;3(6):e94463.
8. Motwani MP, Bennett F, Norris PC, Maini AA, George MJ ... Gilroy DW (2018). Potent Anti-Inflammatory and Pro-Resolving Effects of Anabasum in a Human Model of Self-Resolving Acute Inflammation. Clin Pharmacol Ther. 2018 Oct;104(4):675-686. Epub 2018 Jan 30.
9. Newson J, Motwani MP, Kendall AC, Nicolaou A ... Gilroy DW (2017). Inflammatory Resolution Triggers a Prolonged Phase of Immune Suppression through COX-1/mPGES-1-Derived Prostaglandin E2. Cell Rep. 2017 Sep 26;20(13):3162-3175.
10. Audzevich T, Bashford-Rogers R, Mabbott NA ... Gilroy DW (2017). Pre/pro-B cells generate macrophage populations during homeostasis and inflammation. Proc Natl Acad Sci USA. 2017 May 16;114(20):E3954-E3963.
11. Gilroy DW, Edin ML, De Maeyer RP, Bystrom J, et al (2016). CYP450-derived oxylipins mediate inflammatory resolution. Proc Natl Acad Sci USA. 2016 Jun 7;113(23):E3240-9.
12. Motwani MP, Flint JD, De Maeyer RP, Fullerton JN, Smith AM, Marks DJ, Gilroy DW (2016). Novel translational model of resolving inflammation triggered by UV-killed E. coli. J Pathol Clin Res. 2016 May 4;2(3):154-65.
13. Newson J, Stables M, Karra E, Arce-Vargas F, Quezada S ... Gilroy DW (2014). Resolution of acute inflammation bridges the gap between innate and adaptive immunity. Blood. 2014 Sep 11;124(11):1748-64.
14. O'Brien AJ, Fullerton JN, Massey KA, Auld G ... Gilroy DW (2014). Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat Med. 2014 May;20(5):518-23.
15. Stables MJ, Shah S, Camon EB, Lovering RC ... Gilroy DW (2011). Transcriptomic analyses of murine resolution-phase macrophages. Blood. 2011 Dec 22;118(26):e192-208.
16. Stables MJ, Newson J, Ayoub SS, Brown J, Hyams CJ, Gilroy DW (2010). Priming innate immune responses to infection by cyclooxygenase inhibition kills antibiotic-susceptible and -resistant bacteria. Blood. 2010 Oct 21;116(16):2950-9.

Awards

2005: Bayer International Young Investigator Award for Aspirin Research.

2007: The British Pharmacological Society, Novartis Award.

2018: Election to Fellow of the British Pharmacological Society.

2020: Peter Dressel prize in Pharmacology, University of Nova Scotia, Dalhousie.

Member of the Henry Kunkel Society, New York