Inflammation and Allergy
Monocyte/Macrophage Activation in Chronic/Sterile Inflammation: regulation of cytokine homeostatis
Background: The inflammatory response aims at protecting the organism by clearing out the initial cause of cell injury (e.g., microorganisms or toxins) and the consequences of such injury (e.g., necrotic cells and tissues), and in turn at initiating mechanisms designed at repairing surrounding damaged tissues. Inflammation has to be tightly controlled in time and space to avoid detrimental developments such as those seen in sepsis and chronic inflammatory diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). Monocytes/macrophages play critical parts in non-septic T cell-mediated chronic inflammatory diseases as exemplified by multiple sclerosis (MS) and rheumatoid arthritis (RA). Monocytes/macrophages are the major producers of cytokines at inflammatory sites in both chronic/sterile and acute/infectious inflammation. Cell-cell contact with stimulated T lymphocytes is now considered a major pathway triggering monocytes/macrophages to produce inflammatory mediators in the absence of infectious agents. This mechanism is likely to be relevant to chronic inflammatory diseases, particularly in the perivascular region of local sites of inflammation where T lymphocytes and monocytes/macrophages are in close proximity. This is also the region where apolipoprotein A-I - a specific inhibitor of contact-mediated activation of monocytes - accumulates upon active inflammation.
Aims: The aim of our project is to characterize the molecular basis of cell-cell contact with stimulated T cells as a general strategy whereby monocytes/macrophages are triggered to produce cytokines and to differentiate/maturate. To this purpose we are currently investigating critical aspects of this mechanism by addressing the following questions: A) Which are the ligands on stimulated T lymphocytes and receptors on monocytes involved in the induction of cytokines? B) Which transduction pathways and nuclear factors in monocytes/macrophages are involved in cytokine induction by contact with stimulated T cells and not involved in acute/infectious inflammation? C) Could T cell microparticles ship contact-mediated activation of monocytes away from a distance? D) Is cellular contact with stimulated T cells involved in the differentiation of monocytes into macrophages observed at the inflammatory site? and E) Does contact-mediated activation of monocytes occurs in mouse system in a similar way as in human?
Relevance: MS and RA lead to profound disabilities on which disease-modifying treatments, have shown beneficial effects but are far to cure patients. The specific blockade of T cell contact-mediated activation of monocytes/macrophages, i.e., the blockade of pathogenic, deregulated cytokine production rather than the blockade of cytokine action constitutes a new approach to treating patients, the beneficial functions of cytokines such as that of TNF in remyelination remaining intact. Thus the identification of the extra- and intracellular factors involved in contact-mediated activation of monocyte/macrophages may lead to the characterization of new agents able to interfere with cytokine production and contribute to the identification of novel therapeutic tools and approaches.