Scientific Abstract
Proposal No. IBD-0040R
Principal Investigator: Subrata Ghosh, M.D.
Applicant Organization: Imperial College School of Science, Technology and Medicine (London, United Kingdom)
Project Title: Do dietary microparticles modulate macrophage activation and phagocytosis in Crohn's disease?
Period of Award: September 1, 2003 - April 30, 2005
We have recently reported the presence of inorganic microparticles within the lining of the Crohn’s disease affected intestine removed at surgery. These microparticles are composed of oxides of aluminium, silicon, titanium and chromium. Although other researchers have also described inorganic microparticles in Crohn’s disease tissue (Powell et al. 1996) chromium has been identified for the first time in these particles by the Principal Investigator (Mazumdar et al. 2002). Hexavalent chromium is toxic, but trivalent chromium has more subtle effects, especially in epithelial sensitization. The origin of these particles is dietary and they are widely present in Western processed foods. It is estimated that an individual ingests 1012 fine particles (i.e., bacterial sized microparticles) every day (Powell et al. 2000). These dietary microparticles may potentiate immune responses and overcome lack of intestinal responsiveness to luminal contents.
Microparticles are found within intestinal macrophages following phagocytosis. Inorganic microparticles, especially those containing chromium, can incite inflammatory responses (Pandey et al. 1996). It is important to determine if these microparticles, which may enter the intestinal wall through damaged lining as well as Peyer’s patches, simply reside within the macrophages innocently, or whether they amplify or inhibit the inflammatory role of macrophages. The applicants have proposed a role for microparticles in the etiopathogenesis of Crohn’s disease.
There are potentially at least two mechanisms by which microparticles may affect macrophages to perpetuate chronic intestinal inflammation. The macrophages might be activated to release pro-inflammatory cytokines, which are a hallmark of Crohn’s inflammation. Using 3mm titanium particles, microparticle induced macrophage activation and mediator production has been shown to involve phosphorylation of the protein tyrosine kinase lyn and the phospholipases Cgamma-1 and Cgamma-2 (Palmbos et al. 2002). It is also possible that macrophage phagocytosis of apoptotic bodies and cell debris may be impaired, and this may perpetuate inflammation. This may be due to increased dendritic cell uptake and processing of dead cells provoking T cell immunity. Furthermore, impairment of phagocytic clearance may prevent induction of an anti-inflammatory milieu (such as TGF-b) within the intestinal tissue.
We propose to investigate how the uptake of microparticles by intestinal macrophages affects their function. This project will investigate whether microparticles are pro-inflammatory by co-culturing peripheral blood derived monocytes with microparticles and control polystyrene latex microbeads. In later work, isolated intestinal mononuclear cells will also be used. In particular, we will investigate whether uptake of microparticles might interfere with the immune-suppressive effects of macrophage function consequent on the expression of the newly described phosphatidylserine receptor (PSR). Currently, there is no data on the expression of this receptor in Crohn’s disease.