Galectins are a protein family defined by their affinity for beta-galactosides and consensus protein sequences. These proteins have been identified with diverse biological processes and to function both inside and outside the cell. We discovered the anti-apoptotic function of galectin-3 and substantiated this function by using cells from galectin-3- deficient (gal3-/-) mice. We have demonstrated that exogenously added galectin-3 induces migration of monocytes/macrophages both in vitro and in vivo and obtained preliminary data supporting a role for endogenous galectin-3 in the migration of macrophages. We found that gal3-/- macrophages are defective in FcgammaR-mediated phagocytosis of IgG-opsonized erythrocytes and apoptotic thymocytes both in vitro and in vivo. Confocal microscopic analysis of macrophages containing phagocytosed erythrocytes revealed localization of galectin-3 in the phagosomes. We have obtained a substantial amount of data supporting a role of galectin-3 in defense against microorganisms. Our collaborators found that galectin-3 accumulates in Mycobacterium-containing phagosomes during the course of infection and, more significantly, that gal3-/- mice are severely impaired in their ability to clear the late mycobacterial infection. We also discovered a new galectin family member, galectin-12, and demonstrated its activity in regulation of the cell cycle and cell differentiation. We have obtained data supporting the role of this lectin in the differentiation of macrophages and neutrophils. Thus, the existing information in the literature suggests that galectins play important roles in innate immunity. We will focus in the next funding period on the role of galectins in innate immunity, by addressing the following three specific aims: 1. Elucidation of the mechanism of galectin-3's regulation of phagocytosis 1) establish the role of galectin-3 in maturation of phagosomes 2)elucidate the mechanism by which galectin-3 associates with phagosomes 2. Investigation of the mechanisms by which galectin-3 contributes to host defense against M. tuberculosis 1) establish the role of galectin-3 in monocyte recruitment/granuloma formation in M. tuberculosis infection 2) demonstrate the anti-apoptotic activity of galectin-3 in macrophages infected by M. tuberculosis 3) establish the role of galectin-3 in phagocytosis of apoptotic macrophages infected by M. tuberculosis 4) demonstrate the association between galectin-3 and glycolipids from M. tuberculosis in the cytosol 3. Investigation of the function of galectin-12 in differentiation of macrophages and neutrophils 1) study the effect of the galectin-12 expression on the differentiation of bipotent myeloid cell lines in vitro 2) investigate whether galectin-12 expression affects the determination of cell fate in hematopoitic cells in vivo 3) elucidate the interplay between galectin-12 and major myeloid transcription factors
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