AbstractThe Myeloid differentiation primary response protein (MyD88) plays a central role in innate immune signalling by acting as an adaptor protein downstream of most of the Toll-like receptor (TLR) family and all the IL-1 receptor family members. Activation of MyD88 dependent signalling is critical for the immune response during infections, however dysregulation of these pathways can contribute to the development of immune mediated diseases.
The first aim of my thesis was to understand the role IL-33 signalling type 2 innate lymphoid cells and to identify potential targets to modulate their response. Stimulation of ILC2 cells with IL-33 induced phosphorylation of p38 and ERK1/2 and secretion of IL-13, IL-5, IL-6, IL-9 and GM-CSF. Inhibition of p38 using the specific inhibitor VX745 showed that p38 is crucial for cytokine production in ILC2s. MK2 and MK3, two kinases downstream of p38, were also found to regulate production of IL-6 and IL-13. In addition to cytokine production, stimulation of ILC2 cells with IL-33 induced an increase in ILC2 size and granularity. Moreover, IL-33 stimulated ILC2 cells had a higher uptake of the tryptophan metabolite kynurenine in comparison to unstimulated cells, which was dependent on the amino acid transporter Slc7a5.
The second aim in my thesis was to understand the role of the A20 binding inhibitor of NF-κB (ABIN1) in the development of lupus like autoimmunity in mice. Mice carrying a mutation of Asp485 to Asn in the ubiquitin binding domain of ABIN1 develop spontaneous autoimmunity with hallmarks of SLE including splenomegaly, presence of autoreactive antibodies against nuclear antigens and glomerulonephritis. Characterisation of innate immune populations in ABIN1[D485N] mice showed that these mice have a massive increase of Ly6C-ve patrolling monocytes. Crossing ABIN1[D485N] mice to TLR7, MyD88 knock out mice or to mice with catalytically inactive IRAK1 or IRAK4 kinases prevented the increase in the monocytes, suggesting that a TLR7-MyD88-IRAK4-IRAK1 pathway not only drives lupus in ABIN1[D485N] mice but also increases the number of patrolling monocytes. Targeting this pathway using an IRAK4 specific inhibitor blocked the expansion of the Ly6C-ve patrolling monocytes and the disease development in ABIN1[D485N]
mice. Therefore, inhibition of the IRAK4 kinase could have beneficial effect in SLE patients with mutation in the tnip1 genes or dysregulation of the TLR pathways.
|Date of Award||2019|
|Add any sponsors of the thesis research||Wellcome Trust|
|Supervisor||Simon Arthur (Supervisor)|
Investigating the role of MyD88 signalling pathway in immune mediated diseases
Petrova, T. (Author). 2019
Student thesis: Doctoral Thesis › Doctor of Philosophy