Tartrate resistant acid phosphatase in the immune and nervous system : Distribution and pathophysiological implications

Sammanfattning: Tartrate resistant acid phosphatase (TRAP) belongs to the family of purple acid phosphatases (PAP). It is a glycoprotein synthesized as a monomer with low enzyme activity containing a redox active diiron centre in the active site. Post-translational proteolytic processing of this monomer into a dimeric protein increases the enzyme activity. Traditionally, TRAP has been used as a marker for bone resorbing cells but the biological function of TRAP is still not fully elucidated. However, some studies suggested that also cells outside the skeleton express TRAP and consequently the distribution, characterization and possible functions of TRAP outside the skeleton were addressed in this thesis. Our results show that resident and inflammatory macrophages, certain neurons and epithelial cells express TRAP. Biochemical characterization of extra skeletal TRAPs showed that they contain a redox active di-iron centre, and that proteolytic processing seems to be important for the reduction of this centre. Monomeric TRAP tended to be more highly expressed in epithelial cells compared to cells of the myeloid lineage, but, subpopulations of macrophages i.e. alveolar macrophages and adipose tissue macrophages isolated from hyperplastic obesity also seems to express high amounts of monomeric TRAP. With respect to possible physiological functions, monomeric TRAP was shown stimulate proliferation and differentiation of adipocytes. High expression of monomeric TRAP in human obese adipose tissue macrophages suggests a role of macrophage-derived monomeric TRAP in the development of hyperplastic obesity associated with normal insulin sensitivity and normal lipid- and carbohydrate-metabolism in adipocytes. In macrophages, Th1 cytokines and lipopolysaccaride (LPS) up regulated TRAP expression. Induction of TRAP expression in the early stages of experimental DSS-induced colitis in rats suggests that TRAP could be utilized as a cellular marker of Th1-dependent macrophage activation in inflammatory bowel diseases. In summary, macrophages, certain epithelial cells and neurons express TRAP. Taking into account organ size, the largest contributors of TRAP are bone, spleen and liver. The differential expression of monomeric and proteolytically processed TRAP in a macrophage cell population could influence the biological effects of TRAP to act either as a growth factor or as a modulator of innate immune responses in certain inflammatory conditions.