Macrophage biology

International research group

Hidden immunopathologies play important roles in the development of such life threatening diseases as atherosclerosis, including its consequences (heart attack and stroke), cancer and dementia. Currently there are no drugs available that are capable of normalizing functionality of the immune system. It is obvious that in the case of hidden immunopathology typical for atherosclerosis effective stimulation of immune system will significantly increase the efficacy of traditional therapy and prevention. Several cellular components are responsible for the regulation of the activity of immune system. The key regulatory role in this process is played by monocytes and macrophages (Gordon and Taylor 2005; Burke and Lewis 2002). Being distributed in all tissues and organs of the human body macrophages control its condition and guarantee timely and effective reaction to damage, pathogen intrusion or transformed cell appearance. After effective inflammatory reaction and removal of the danger macrophages initiate healing processes and restore tissue homeostasis (Gratchev et al., 2006). Thus malfunction of macrophages underlines most immune disorders (Hansson 2005; Bingle et al., 2002). In spite of rapid development of biomedical technologies up to date there is no reliable test system for the complex analysis of the activity of various cellular components of human immunity. It is highly important to develop an universal, reliable and affordable system for the assessment of the condition of human immune system on the basis of primary human monocyte derived macrophages. We and others have established that macrophages may adapt their phenotype to changing microenvironment (Stout and Suttles 2004; Gratchev et al., 2006). According to their pro- and anti-inflammatory activity macrophages can be classified as type 1 (M1) and type 2 (M2) respectively (Gratchev et al., 2001). Various pro- and anti-inflammatory stimuli are responsible for high heterogeneity of macrophage phenotype in each class. Type 1 macrophages produce pro-inflammatory cytokines TNF and IL-1beta and express Fc-gamma receptors on the cell surface (Gordon et al., 1995; Gratchev et al., 2001). Type 2 macrophages produce anti-inflammatory cytokines and chemokines IL-1ra, IL-10, CCL18 and express various scavenger receptors on the surface (Gratchev et al., 2001; Gratchev et al., 2001; Gordon 2003; Gratchev et al., 2005). The mechanism of macrophage activation is highly complex and includes several signalling cascades, vesicular trafficking and interaction of these two processes (Kzhyshkowska et al., 2006; Kzhyshkowska et al., 2006; Gratchev et al., 2008; Kzhyshkowska et al., 2008; Park et al., 2009; Zhang et al., 2009). In case of immune system dysfunction blood monocytes that have to be in inactive state gain properties of activated macrophages and change their surface markers (Mosig et al., 2009). Therefore the analysis of the balance between pro- and anti-inflammatory activities of primary human monocyte-derived macrophages is an attractive possibility for identification of hidden immunopathologies. The test system for the complex analysis of activation state of primary human monocytes may be instantly used for the development of an immuno-correcting anti-atherosclerotic drug on the natural substance basis that will be used for prevention and treatment of atherosclerosis. Following arguments are taken into account: (1) the problem addressed in the project is socially important due to the prevalence of atherosclerosis and its consequences (heart attack, stroke) in Russian and European populations; (2) it is necessary to develop a novel cell-based test system for the analysis of immuno-correcting properties of natural substances; (3) desired test system has to be develop on the beyond-state of the art level using latest developments in immunology, medicine and nanothechnology; (4) the test-system has to be universal and has to have a potential for development of a novel drugs for immuno-correction; (5) development of drugs for immuno-correction has to take into account knowledge about existing anti-inflammatory drugs.