Helminth parasites are complex multicellular organisms capable of maintaining long lasting, chronic infections in human hosts. To ensure their survival and successful reproduction, helminth parasites have developed immunomodulatory mechanisms to modulate their hostÃÂ¢ÃÂÃÂs immune system to minimise the physical and immunological pathology to the host and prevent parasite expulsion. Many cells of the immune system are targets for parasite mediated immune modulation including T cells, macrophages and dendritic cells. Further, many inflammatory diseases feature an imbalance between the main subsets of macrophages, M1 and M2, in favour of the M1 pro-inflammatory phenotype. Also, many helminth products have been shown to be able to skew immune responses away from M1 macrophages, thus potentially attenuating disease progression. Therefore, the excretory/secretory products (ES) of the adult stage of the gastrointestinal nematode parasite Trichuris muris have been studied to explore their potential to modulate macrophage biology. Bone marrow derived macrophages (BMDM) were selected to (a) evaluate the ability of T. muris ES to down regulate pro-inflammatory macrophage responses; (b) explore the intracellular mechanisms underlying any immunomodulatory activity and (c) assess the potential of ES molecules to confer protection from inflammatory and autoimmune disorders. Pre-treatment of murine BMDMs with T. muris ES and its fractions significantly suppressed the expression of the pro-inflammatory mediators TNF, IL-27, CCL2, IL-6, IL-IÃÂÃÂ², and Nos2 upon LPS stimulation. T. muris ES also reduced the phosphorylation of p65 at serine 536, downregulated the expression of the histone acetyl transferase (HAT) p300 family, and upregulated the expression of histone deacetylases (HDACs). Moreover, bone marrow cells differentiated to BMDM in the presence of T. muris ES reduced the inflammatory responses of the mature BMDM through modifying the expression of the epigenetic enzymes (HATs and HDACs), with these effects of ES being reversed by epigenetic inhibitors. ES also increased the expression of macrophage cell surface markers on differentiated BMDMs. T. muris ES suppressed multiple LPS-driven genes in the TLR signalling pathway of both murine BMDM pre-incubated with ES, and BMDM derived from ES-exposed bone marrow cells. Ingenuity pathway analyses suggested the involvement of intracellular pathway regulators that orchestrate the expression of the inflammatory genes. Thus, T. muris ES has the potential to limit the pathology associated with inflammatory and autoimmune diseases.
|Date of Award
|1 Aug 2019
- The University of Manchester
|Richard Grencis (Supervisor) & Kathryn Else (Supervisor)