Signaling networks regulating leukocyte podosome dynamics and function

Podosomes are ventral adhesion structures prominent in cells of the myeloid lineage. A common aspect of these cells is that they are highly motile and must to traverse multiple tissue barriers in order to perform their functions. Recently podosomes have gathered attention from researchers as important cellular structures that can influence cell adhesion, motility and matrix remodeling. Adhesive and soluble ligands act via transmembrane receptors and propagate signals to the leukocyte cytoskeleton via small G proteins of the Rho family, tyrosine kinases and scaffold proteins and are able to induce podosome formation and rearrangements. Manipulation of the signals that regulate podosome formation and dynamics can therefore be a strategy to interfere with leukocyte functions in a multitude of pathological settings, such as infections, atherosclerosis and arthritis. Here, we review the major signaling molecules that act in the formation and regulation of podosomes.     

Macrophage differentiation and granulomatous inflammation in osteopetrotic mice (op/op) defective in the production of CSF-1

Since the osteopetrotic (op/op) mouse was demonstrated to have a mutation within the coding region of the CSF-1 gene itself, it serves as a model for investigating the differentiation mechanism of macrophage populations in the absence of functional CSF-1. The op/op mice were severely monocytopenic and showed marked reduction and abnormal differentiation of tissue macrophages. Osteoclasts as well as marginal metallophilic macrophages and marginal zone macrophages in the spleen were absent. Most of the tissue macrophages were reduced in number and ultrastructurally immature. However, the degree of reduction in numbers of macrophages in the mutant mice was variable among tissues, suggesting that the heterogeneity of macrophages was generated by their different dependency on CSF-1. After daily CSF-1 injection, the numbers of monocytes, tissue macrophages, and osteoclasts were remarkably increased, and the macrophages showed morphological maturation. However, the numbers of macrophages in the ovary, uterus, and synovial membrane were not increased. In the bone marrow, macrophage precursors detected by monoclonal antibody ER-MP58 proliferated and differentiated into preosteoclasts and osteoclasts. In the spleen, marginal metallophilic macrophages and marginal zone macrophages developed slowly. In this manner, CSF-1 plays an important role in the development, proliferation, and differentiation of certain tissue macrophage populations and osteoclasts. In the op/op mice, Kupffer cells proliferated, transformed into epithelioid cells and multinucleated giant cells, and participated in glucan-induced granuloma formation. In CSF-1-treated op/op mice, the process of granuloma formation was similar to that in normal littermates due to increased monocytopoiesis and monocyte influx into the granulomas. These results indicate that CSF-1 is a potent inducer of the development and differentiation of CSF-1-dependent monocyte/macrophages, and that CSF-1-independent macrophages also play an important role in granuloma formation. Mol Reprod Dev 46:85–91, 1997. © 1997 Wiley Liss, Inc.     

OCILRP2 signaling synergizes with LPS to induce the maturation and differentiation of murine dendritic cells

Osteoclast Inhibitory Lectin-related Protein 2 (OCILRP2) is a typical type II transmembrane protein and belongs to C-type lectin-related protein family. It is preferentially expressed in dendritic cells (DC), B lymphocytes, and activated T lymphocytes. Upon binding to its ligand, OCILRP2 can promote CD28-mediated co-stimulation and enhance T cell activation. However, the role of OCILRP2 in DC development and activation is unclear. In this report, we present evidence that recombinant protein OCILRP2-Fc inhibits the generation and LPS-induced maturation of murine bone marrow-derived dendritic cells (BMDCs) by downregulating the expression of CD11c, MHC-II, and co-stimulators CD80 and CD86. OCILRP2-Fc also reduces the capacity of BMDCs to take up antigens, activates T cells, and secret inflammatory cytokines such as IL-6, IL-12, and TNF-α. Additionally, we show that OCILRP2-Fc may cause the aforementioned effects through inhibiting NF-κB activation. Therefore, OCILRP2 is a new regulator of DC maturation and differentiation following TLR4 activation.