Final Activity Report Summary - MCCID (Mast Cells and Chronic Inflammatory Disease (MCCID): a PhD research training project for combined fundamental and clinical investigation)
Mast cells (MCs) are cells of haematopoietic origin exclusively localised to tissues. In addition to their well-recognised role in IgE-mediated allergies, recent evidences demonstrated their implication in a variety of human inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, fibrosis and even cancer. The MCCID network was designed as a training programme for early stage researchers, aiming to analyse the role of MCs in inflammatory diseases of various tissues using either animal models or clinical samples, to tackle the question on the interrelationship between MCs and the disease process and to study inflammatory mediator release by MCs at the molecular level. The progress made can be summarised in several points reflecting the programme structure:
1. studies of the role of MCs in experimental inflammatory disease models using MC or mediator-deficient mice put into light the dual face of MC involvement in inflammatory mechanisms which could be either protective or disease aggravating. As an example, while MCs protected against experimental glomerulonephritis, certain MC-derived mediators, e.g. the protease MCP-4, might rather aggravate the disease. This indicated a complex relationship between different mast cell products and the physiological disease context. A possible role of MCs in atherosclerotic plaque formation was not confirmed.
2. studies investigating the disease mechanisms were tackled in both animal models and patient samples. It was shown that, during cutaneous inflammation, CD30 ligand was upregulated in human skin MCs so as to mediate degranulation-independent chemokine secretion. CD30 ligand activation of MCs could also play a role in tumorigenesis in basal cell carcinoma as well as in rheumatoid arthritis. Furthermore, it was shown that certain carcinoma cells were resistant to the cytotoxic effect of MC mediators, while normal primary keratinocytes were not. In multiple sclerosis it was demonstrated that the disease aggravating role of MCs might involve their direct activation by myelin through expressed scavenger receptors. In gastrointestinal diseases the cross-talk between human gastrointestional fibroblasts and MCs was investigated, as it could play a role in pathophysiology. It was found that fibroblast-secreted IL-6 prevented apoptosis of human MCs, and that MC mediators induced fibroblasts to secrete metalloproteinase-1 involved in tissue remodelling and fibrosis development. In the conjunctiva of the eye it was shown that stimulation of chemokine receptors enhanced the allergic stimulation through the IgE receptor and therefore also enhanced allergy symptoms. Furthermore, maturing human MCs were shown to secrete pro-inflammatory and anti-inflammatory cytokines in the absence of stimulation, indicating that they might not be innocent bystanders.
3. molecular studies in in vitro cellular models revealed an important function of granular constituents, such as serglycin proteoglycans, which were important for the correct storage of inflammatory mediators in MC granules as well as for granule integrity in different haematopoietic cells including MCs. As a result, serglycin-deficient mice showed deficiencies in the haematopoietic compartment. In another study it was shown that certain fusion regulating proteins expressed on mast cell granules such as VAMP-8 and Munc18 were involved in the release of inflammatory mediators from granules but not for the release of inflammatory cytokines. A study of the molecular crosstalk between chemokine receptor CCR1 and the IgE receptor signalling in MCs was performed using gene expression profiling. Initial results revealed a series of synergy-related genes that were partially validated in functional studies.
Finally, the network enabled the training of young researchers in a privileged setting to obtain, either directly or in the near future, their doctoral degrees as well as to establish a continuous European partnership and task force for future challenges in the field.
1. studies of the role of MCs in experimental inflammatory disease models using MC or mediator-deficient mice put into light the dual face of MC involvement in inflammatory mechanisms which could be either protective or disease aggravating. As an example, while MCs protected against experimental glomerulonephritis, certain MC-derived mediators, e.g. the protease MCP-4, might rather aggravate the disease. This indicated a complex relationship between different mast cell products and the physiological disease context. A possible role of MCs in atherosclerotic plaque formation was not confirmed.
2. studies investigating the disease mechanisms were tackled in both animal models and patient samples. It was shown that, during cutaneous inflammation, CD30 ligand was upregulated in human skin MCs so as to mediate degranulation-independent chemokine secretion. CD30 ligand activation of MCs could also play a role in tumorigenesis in basal cell carcinoma as well as in rheumatoid arthritis. Furthermore, it was shown that certain carcinoma cells were resistant to the cytotoxic effect of MC mediators, while normal primary keratinocytes were not. In multiple sclerosis it was demonstrated that the disease aggravating role of MCs might involve their direct activation by myelin through expressed scavenger receptors. In gastrointestinal diseases the cross-talk between human gastrointestional fibroblasts and MCs was investigated, as it could play a role in pathophysiology. It was found that fibroblast-secreted IL-6 prevented apoptosis of human MCs, and that MC mediators induced fibroblasts to secrete metalloproteinase-1 involved in tissue remodelling and fibrosis development. In the conjunctiva of the eye it was shown that stimulation of chemokine receptors enhanced the allergic stimulation through the IgE receptor and therefore also enhanced allergy symptoms. Furthermore, maturing human MCs were shown to secrete pro-inflammatory and anti-inflammatory cytokines in the absence of stimulation, indicating that they might not be innocent bystanders.
3. molecular studies in in vitro cellular models revealed an important function of granular constituents, such as serglycin proteoglycans, which were important for the correct storage of inflammatory mediators in MC granules as well as for granule integrity in different haematopoietic cells including MCs. As a result, serglycin-deficient mice showed deficiencies in the haematopoietic compartment. In another study it was shown that certain fusion regulating proteins expressed on mast cell granules such as VAMP-8 and Munc18 were involved in the release of inflammatory mediators from granules but not for the release of inflammatory cytokines. A study of the molecular crosstalk between chemokine receptor CCR1 and the IgE receptor signalling in MCs was performed using gene expression profiling. Initial results revealed a series of synergy-related genes that were partially validated in functional studies.
Finally, the network enabled the training of young researchers in a privileged setting to obtain, either directly or in the near future, their doctoral degrees as well as to establish a continuous European partnership and task force for future challenges in the field.