Modulation of the Gastrointestinal Immune Environment by Macrophage Migration Inhibitory Factors (MIF) and Helminth-Derived Cytokine Homologues of MIF

PhD Thesis

Neville, M. 2020. Modulation of the Gastrointestinal Immune Environment by Macrophage Migration Inhibitory Factors (MIF) and Helminth-Derived Cytokine Homologues of MIF. PhD Thesis University of East London School of Health, Sport and Bioscience
AuthorsNeville, M.
TypePhD Thesis

Macrophage Migration Inhibitory Factor (MIF) is a pleotropic cytokine first discovered over 50 years ago. MIF and many MIF-like proteins contain an evolutionarily conserved proline residue that confers an enigmatic tautomerase activity. Mammalian MIF proteins also contain an additional oxidoreductase domain whose activity is abrogated by substitution of two critical cysteine residues at position 57 and 60. MIF is secreted constitutively by intestinal epithelial cells and is highly upregulated when barrier function is compromised such as in the case of inflammatory bowel diseases. MIF homologues are also secreted by many parasitic organisms, one of which is the intestinal helminth, Trichinella spiralis. T. spiralis secretes vast quantities of MIF upon entering the gastrointestinal tract though to date the biological relevance of T. spiralis derived MIF in modulating host responses is undetermined.
In this study the generation MIF proteins and mutants devoid of enzymatic sites enabled the analysis of MIF’s role within the intestinal immune environment including the transcriptomic assessment of ex vivo intestinal explants and primary macrophages. Recombinant WT and tautomerase deficient proteins generated as part of this body of work modulated TLR-4 mediated NF-kB activation in the presence of LPS in a HEK and HT29 cell model indicating that MIF can modulate epithelial driven immune responses via a master regulator. Consistent with this, ex vivo studies utilising murine intestinal explants revealed that murine and Trichinella derived MIF homologues modulate cytokines such as IL-6, TNF-a and IL-22 to drive distinct immune responses. In addition, the modulation of IL-22 and TNF-a was highly dependent on the presence of the tautomerase site for Mm-MIF-1 and Ts-MIF-1, respectively. Likewise, analysis of cytokine profiles from MIF treated macrophages in the presence of TLR4 ligand, LPS, confirmed MIF’s role in modulating immune responses.
Further characterization of BMDM macrophages using RNA seq technologies demonstrated that MIF homologues, and in particular, the tautomerase site, modulate the macrophage transcriptome priming cells for two discrete responses upon pattern recognition receptor (PRR) activation. Mm-MIF-1 treated BMDM macrophages downregulated several genes associated with the TNF-a processing and secretion, ADAM28, Trp63 and Rab27b. Conversely, the parasite-derived Ts-MIF-1 upregulated genes responsible for cell cycle regulation, differentiation and cellular architecture such as IGFBP2, BMP3, BMP7 and several Krt genes.
Overall, the data presented in this thesis provides clear evidence of discrete roles for murine and parasite-derived MIF in modulating innate immune responses and demonstrates that, while the activity of the tautomerase site is context dependent, loss of the enzymatic activity leads to dysregulation MIF responses.

PublisherUniversity of East London
Digital Object Identifier (DOI)
File Access Level
Publication dates
Online10 Dec 2020
Publication process dates
SubmittedDec 2020
Deposited10 Dec 2020
Permalink -

Download files

License: CC BY-NC-ND 4.0
File access level: Anyone

  • 133
    total views
  • 173
    total downloads
  • 0
    views this month
  • 1
    downloads this month

Export as

Related outputs

Student showcase
Rodriguez, Oscar, Eguara, Omafuvwe, Hillson, Olivia, Gajewski, Jessica, Petkovic, Ana, Wilson, Shantal, Kolawole, Bridget, Bierman, Anne Nicole, Lazar, Nicoleta, Engelke, Fabienne, Santosh, Jaishaal, Kolade, Deborah, Uthman, Omobola, Ramli, Marhaini, Apete, Adjoua Anais Diana, Ogundero, Ibironke Aminat, Martins Neto, Daniela, Hosen, Kamal, Nusrat, Sanna, Rashid, MD Amanur, Sungurov, Stanislav, Chowdhury, Badrun Naher, Khalid, Maryam, Tanvir, Mohammad, Hasan, MD Oliul, Fahad, MD Yasin AL, Wabara, Nnena Abiola, Rashid, MD, Olomu, Edith, Vincent, Chiamaka, Winegarner, Lukas, Adejonwo, Joseph, Bunic, Tanja, Murdoch, Maximilian, Hasan, Shaikh, Emmanuel, Solomon M., Ghai, Rupali, Gospodinov, Miroslav, Popoola, Adenike, Rizki, Reza, Coulibaly, Chigata, Husain, Laila, Di Palma, Amelia, Oluwadare, Sunday, Amkssa, Jamel, Kolosova, Alina, Neville, M., Diarra, Binta, Opaluwa, Joshua A., Osuagwu, Ikenna Bret, Wilson, Taylor A., Agbaje, Olubunmi A., Ajayi, Festus Adeolu, Alrajhi, Omar Hamad, Leworthy, Brigid Elizabeth, Olsen, Sissel, Omofomwan, Sheila, Salihu, Aminu Salihu, Sani, Kareem Folohunso, Okafor, Chidinma J., Krnjetin, Milan, Lindinger, Michaela, Abd Halim, Sarah, Anso, Helen S., Cap, Kim Hoang, James, Eme P., Javaid, Muhammad Rahat, Kwabo, Fodio Umar, Naeem, Wahab, Nguyen, Thuy Thanh, Raffa, Mohamed Karim, Singh, Shristi, Alele, Oluwaseun Abiodun, Mcphail, James, Kin, Min Shiew, Skarra, Kostandina, Kusuv, Sezer, Ajidahun, Adebola Oluwakemi, Atigeh Chian, Milan, Dolan, Callum, Emmanuel, Enukorah, Ghanei, Ali, Jakkal, Raj Madhukar, Khan, Luqman, Kuvshinskiy, Dmitry, Madziga, Hannah Timtak, Nguyen, Ngoc Kim Chi, Obi, Lynda C., Parmar, Puneet, Silver, Toni O., Yerlan, Agaidarov, Abid, Usman, Alegbejo, Titilayo B., Asimadi, Isabella, Guedes de Mello, Leonardo, Ibrahim, Nasiru Aminu, Kaysi, S. Serhat, Reihanisardhai, Mahsa, Samiullah, Jadoon, Sears, Jonathan D. B. and Malaekeh, Behrooz Student showcase.
The Interplay between Hedgehog Signalling and BMP Signalling in Regulating B cell Development
Neville, M. 2015. The Interplay between Hedgehog Signalling and BMP Signalling in Regulating B cell Development. Masters Thesis University of East London Health, Sports and Bioscience
Development of a Novel Vaccine Delivery Platform Using Probiotic Yeasts
Neville, M. 2014. Development of a Novel Vaccine Delivery Platform Using Probiotic Yeasts. UEL Undergraduate Research Internships. University of East London.