Tissue-protective cytokines

Wound healing remains a major problem, particularly in diabetes where 100 people in the UK lose a limb each week. High rates of foot ulceration are also seen in inflammatory arthropathies such as rheumatoid arthritis.

In diabetes this is associated with loss of intra-epidermal nerve fibres and significant co-morbidities, such as vascular impairment and kidney disease. At the molecular level, several mediators (called cytokines) are essential for the body to survive infections by killing bacteria (resistance) or withstanding the damage they cause (tolerance). The research team at the University of Brighton and Brighton and Sussex Medical School recently identified cytokines that stimulate repair and protect from damage, and termed them tissue-protective cytokines.

Tissue-protective cytokines have been described mainly in the context of neurorepair. Here we plan to exploit their activities in wound and nerve injury.

The teams research plan also undertook characterising tissue repair small molecules (peptides) derived from these cytokines that could be used as therapeutics, as such or onto biomaterials (e.g. dressings, nerve guides).

The project team tested these cytokines, and their interaction with inflammation, in two models:

> in vitro model of wound healing; and
> an in vitro model of remyelination (nerve repair).

The project team identified one pro-myelinating cytokine and progressed to performing a gene expression profiling experiment to show exactly which genes mediate the reparative action of tissue-protective cytokines. They also identified their mechanism of action, the signalling mechanisms they activate in oligodendrocytes (the cell producing the myelin sheath).

The team set up an in vitro model of wound healing in endothelial cells and demonstrated a reparative function of tissue-protective cytokines. We will soon expand these studies to primary skin cells and, in the future, performing a gene expression profiling also in this model.

These studies allow researchers to define tissue-protective cytokines, conceptually and at a molecular level, and their role in skin and nerve repair. The date obtained with small peptides was predicted to lead the way to new treatments.

The research team also performed a bioinformatics analysis of several cytokines to help define a family of tissue-protective cytokines. This new research afforded an opportunity to explore new models of tissue healing. More rapid healing would not only potentially reduce amputation rates but also improve patients’ quality of life, which is typically negatively affected by the impact of chronic wounds and peripheral neuropathies.

Publications

Mengozzi M, Ermilov P, Annenkov A, Ghezzi P, Pearl F. Definition of a Family of Tissue-Protective Cytokines Using Functional Cluster Analysis: A Proof-of-Concept Study. Front Immunol. 2014 Mar 17;5:115. doi: 10.3389/fimmu.2014.00115. eCollection 2014. PubMed PMID: 24672526; PubMed CentralPMCID: PMC3955874.

Cervellini I, Annenkov A, Brenton T, Chernajovsky Y, Ghezzi P, Mengozzi M. Erythropoietin (EPO) increases myelin gene expression in CG4 oligodendrocyte cells through the classical EPO receptor. Mol Med. 2013 Aug 28;19:223-9. doi: 10.2119/molmed.2013.00013. PubMed PMID: 23821361; PubMed Central PMCID:PMC3769529.

Gyetvai G, Mengozzi M, Annenkov A, Ghezzi P “LIF increases myelination but inhibits the myelinating effect of EPO in oligodendrocyte precursor cells“. British Society of Immunology, Conference December 2014 (manuscript in preparation)

L.Heikal, P.Ghezzi, G.Ferns. The effects of Erythropoietin (EPO) and its carbamylated derivative (CEPO) are enhanced under hypoxic conditions in a wound injury model. Manuscript in preparation.