Investigating the regulation of neutrophil gene expression by intracellular signalling and small non-coding RNAs


Immune-mediated inflammatory diseases (IMID) such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) affect millions of people worldwide and cause debilitating and disabling musculoskeletal disease. Neutrophils are innate immune cells that play an essential role in the first line host response to infection. However, inappropriate neutrophil activation in IMID drives the inflammatory response through secretion of cytokines and chemokines, and damages host tissue by degranulation of proteolytic enzymes (e.g. MMP8, elastase). In IMID, neutrophil production of reactive oxygen species (ROS) further damages host tissues. The externalisation of post-translationally modified proteins and DNA in neutrophil extracellular traps (NETs) leads to the production of auto-antibodies e.g. auto-antibodies to cyclic citrullinated peptides (ACPA) in RA and dsDNA antibodies in SLE.

Neutrophil gene expression is altered in IMID leading to altered and pathogenic cell function. In RA, blood neutrophils express mRNA for MHC Class II, and synovial fluid neutrophils express high levels of chemokines. This altered neutrophil phenotype drives activation of innate and adaptive immune cells in IMID and causes damage to tissues e.g. in the joints and kidneys. RA and SLE neutrophils have a strong interferon (IFN)-induced gene expression signature. However, IFN protein is not detected in RA or SLE sera. Interestingly, NET debris (myeloperoxidase:DNA complexes) is elevated in RA and SLE blood and NET debris is responsible for IFN production by dendritic cells via toll-like receptor (TLR) activation. Our bioinformatics analysis predicts that RA and SLE neutrophils are activated by TLRs and inflammasomes. Our bioinformatics analysis has also predicted that small and long non-coding RNAs are regulating gene expression in IMID neutrophils. We recently obtained pilot small RNA sequencing data showing that expression of small non-coding RNAs (miRNA, snoRNA, snRNA, tRNA, piwiRNA and tRNAf) is different in RA compared to healthy neutrophils. The effect of small non-coding RNAs on neutrophil function has not yet been investigated.

Our hypothesis is that altered neutrophil gene expression in IMID is regulated by signalling factors such as NET debris activating TLRs on neutrophils leading to expression of IFN-response genes. We also hypothesise that as yet unknown factors alter the expression of small non-coding RNAs, leading to altered gene expression and proinflammatory functions.

The objectives of this project will be to (i) investigate the regulation of neutrophil gene expression and function in IMID by neutrophil signalling products including ROS and NETs, (ii) identify factors altering the expression of small non-coding RNAs in healthy and IMID neutrophils and (iii) determine the functional effect of altered small non-coding RNA expression.

We will combine bioinformatics analysis of RNAseq datasets with in vitro experiments using human neutrophils from healthy controls and people with IMID to measure altered gene and small non-coding RNA expression as well as the effect of the altered expression on neutrophil functions such as ROS production, NET release, apoptosis, phagocytosis and bacterial killing.

This work will advance our understanding of neutrophil physiology in IMID and contribute to a program of research focussed on the development of therapeutic targeting of unwanted neutrophil activation in inflammation, inflammageing and IMID.


To apply: please send your CV and a covering letter to Dr Helen Wright


Open to students worldwide

Funding information

Self-funded project

The successful applicant will be expected to provide the funding for tuition fees, living expenses, and attendance at conferences. A research bench fee of £10,000 p.a. will be levied as a contribution to laboratory consumables and research facility access. There is NO institutional funding attached to this project. Details of costs can be found on the University website.



  1. Zhou Y, Nomigni MT, Gaigneaux A, Tolle F, Wright HL, Bueb JL, Bréchard S. miRNA-132-5p mediates a negative feedback regulation of IL-8 secretion through S100A8/A9 downregulation in neutrophil-like HL-60 cells. Frontiers in Immunology 2023 (in press) doi: 10.3389/fimmu.2023.1274378
  2. Wright HL, Lyon M, Chapman EA, Moots RJ, Edwards SW. Rheumatoid arthritis synovial fluid neutrophils drive inflammation through production of chemokines, reactive oxygen species and neutrophil extracellular traps. Frontiers in Immunology 2021, 11:584116.
  3. Fresneda Alarcon M, McLaren Z, Wright HL*. Neutrophils in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus: same foe different M.O. Frontiers in immunology 2021 12:649693. doi: 10.3389/fimmu.2021.649693