Macrophages in the embryo and beyond: Much more than just giant phagocytes
ABSTRACT Originally recognized as an essential part of the innate and acquired immune systems, macrophages emerged as omnipresent and influential regulators of embryo- and organo-genesis, as well as of tissue and tumor growth. Macrophages are present essentially in all tissues, beginning with embryonic development and, in addition to their role in host defense and in the clearance of apoptotic cells, are being increasingly recognized for their trophic function and role in regeneration. Some tissue macrophages are also found to posses a substantial potential for autonomous self-renewal. Macrophages are associated with a significant proportion of malignant tumors and are widely recognized for their angiogenesis-promoting and trophic roles, making them one of the new promising targets for cancer therapies. Recent expression profiling of embryonic macrophages from different tissues revealed remarkable consistency of their gene expression profiles, independent of their tissue of origin, as well as their similarities with tumor-associated macrophages. Macrophages are also capable of fusion with other cells in tissue repair and metastasizing tumors, as well as with each other in the immune response and osteoclastogenesis. genesis 46:447–462, 2008. © 2008 Wiley-Liss, Inc.
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ABSTRACT: Colony-stimulating factor (CSF)-1 controls the survival, proliferation, and differentiation of macrophages, which are recognized as scavengers and agents of the innate and the acquired immune systems. Because of their plasticity, macrophages are endowed with many other essential roles during development and tissue homeostasis. We present evidence that CSF-1 plays an important trophic role in postnatal organ growth and kidney repair. Notably, the injection of CSF-1 postnatally enhanced kidney weight and volume and was associated with increased numbers of tissue macrophages. Moreover, CSF-1 promotes postnatal renal repair in mice after ischemia-reperfusion injury by recruiting and influencing macrophages toward a reparative state. CSF-1 treatment rapidly accelerated renal repair with tubular epithelial cell replacement, attenuation of interstitial fibrosis, and functional recovery. Analysis of macrophages from CSF-1-treated kidneys showed increased expression of insulin-like growth factor-1 and anti-inflammatory genes that are known CSF-1 targets. Taken together, these data suggest that CSF-1 is important in kidney growth and the promotion of endogenous repair and resolution of inflammatory injury.American Journal Of Pathology 09/2011; 179(3):1243-56. · 4.52 Impact Factor
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ABSTRACT: Csf1r mRNA in adult mice is expressed in cells of the macrophage lineage, and during development, it is also expressed from a separate promoter in placental trophoblast cells. This mouse trophoblast promoter sequence is conserved across species, but human trophoblasts actually initiate transcription from a separate promoter 20 kb upstream, which is not conserved in rodents. A 7.2-kb fragment of the mouse Csf1r genomic DNA, including the 3.5-kb promoter, the first coding exon and downstream intron, is sufficient to direct reproducible position- and copy number-independent expression of an EGFP reporter in vitro and in vivo. In this study, we have examined the consequence of removal of the 150-bp fragment encompassing the conserved trophoblast promoter region in the context of the 7.2-kb promoter on reporter gene expression in transgenic mice. The deletion ablated expression in the placenta but also abolished expression in multinucleated OCL and reduced expression in macrophages. RT-PCR analyses of Csf1r mRNA revealed that mouse OCL use another promoter within this region, distinct from that used in placental trophoblasts, to generate an alternative 5'UTR.Journal of leukocyte biology 05/2010; 87(5):815-22. · 4.99 Impact Factor
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ABSTRACT: Bronchopulmonary dysplasia is a common pulmonary complication of extreme prematurity. Arrested lung development leads to bronchopulmonary dysplasia, but the molecular pathways that cause this arrest are unclear. Lung injury and inflammation increase disease risk, but the cellular site of the inflammatory response and the potential role of localized inflammatory signaling in inhibiting lung morphogenesis are not known. In this study, we show that tissue macrophages present in the fetal mouse lung mediate the inflammatory response to LPS and that macrophage activation inhibits airway morphogenesis. Macrophage depletion or targeted inactivation of the NF-κB signaling pathway protected airway branching in cultured lung explants from the effects of LPS. Macrophages also appear to be the primary cellular site of IL-1β production following LPS exposure. Conversely, targeted NF-κB activation in transgenic macrophages was sufficient to inhibit airway morphogenesis. Macrophage activation in vivo inhibited expression of multiple genes critical for normal lung development, leading to thickened lung interstitium, reduced airway branching, and perinatal death. We propose that fetal lung macrophage activation contributes to bronchopulmonary dysplasia by generating a localized inflammatory response that disrupts developmental signals critical for lung formation.The Journal of Immunology 09/2011; 187(5):2740-7. · 5.52 Impact Factor