Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

Mononuclear phagocytes play a major role in the development of vascular lesions in atherogenesis. The goal of our study was to characterize circulating blood monocyte subpopulations as potential cellular markers of systemic immunological abnormalities in hypercholesterolemia. In normal subjects, three-parameter immunophenotyping of whole blood revealed that 61.3±6.0% of monocytes showed “bright” expression of the lipopolysaccharide receptor (LPSR: CD14) and Fcγ receptor I (RI: CD64) without expression of Fcγ-RIII (CD16). Other monocyte subsets (populations 2, 3, 4, and 5) were characterized by the simultaneous expression of both Fcγ-R's (25.6±5.0%), isolated expression of Fcγ-RIII (9.4±1.7%), or high expression of CD33 (3.7±1.1%) with only dim expression of CD14, respectively. The smallest subset of monocytes (population 5: 2.1±0.8%) differed from the predominant population of CD14brightCD64+CD16− monocytes by additional expression of neural cell adhesion molecule (N-CAM: CD56). In a group of hypercholest...

Peripheral Blood Mononuclear Phagocyte Subpopulations as Cellular Markers in Hypercholesterolemia

Monocytes are primitive hematopoietic cells that primarily arise from the bone marrow, circulate in the peripheral blood and give rise to differentiated macrophages. Over the past two decades, considerable attention to monocyte diversity and macrophage polarization has provided contextual clues into the role of myelomonocytic derivatives in human disease. Until recently, human monocytes were subdivided based on expression of the surface marker CD16. “Classical” monocytes express surface markers denoted as CD14++CD16− and account for greater than 70% of total monocyte count, while “non-classical” monocytes express the CD16 antigen with low CD14 expression (CD14+CD16++). However, recognition of an intermediate population identified as CD14++CD16+ supports the new paradigm that monocytes are a true heterogeneous population and careful identification of specific subpopulations is necessary for understanding monocyte function in human disease. Comparative studies of monocytes in mice have yielded more dichotomous results based on expression of the Ly6C antigen. In this review, we will discuss the use of monocyte subpopulations as biomarkers of human disease and summarize correlative studies in mice that may yield significant insight into the contribution of each subset to disease pathogenesis.

Clinical significance of monocyte heterogeneity

Site-Selective Glycosylation of Cysteine-93 beta on the Surface of Bovine Hemoglobin and its Application as a Novel Oxygen Therapeutic

Local overexpression of monocyte chemoattractant protein-1 at vessel wall induces infiltration of macrophages and formation of atherosclerotic lesion synergism with hypercholesterolemia

This project utilises the chemokine, CCL2, to build a selective delivery platform to target disease-causing monocyte subsets. Monocytes are white blood cells which form part of the innate immune system and are primarily responsible for pathogen engulfment and antigen presentation towards members of the adaptive immune system. Monocytes have been identified in a number of diseases such as liver fibrosis, rheumatoid arthritis and can even be recruited by cancers leading to tumour-protection from the immune system through socalled Tumour-Associated Macrophages (TAMs) and Myeloid-Derived Suppressor Cells (MDSCs). Interestingly, many of these diseases are caused by specific subsets of monocytes which express high levels of the chemokine receptor CCR2. This project has developed CCL2 as a delivery vehicle such that these monocyte subsets can be selectively targeted for fluorophore delivery. A series of CCL2 mutant sequences were conjugated with a range of fluorophores using click chemistry and these conjugates exhibited retained chemotactic function. This chemotaxis and intemalisation of the ligand is CCR2-mediated and disease-causing monocyte subsets were also shown to be targeted with the fluorescent chemokines. Finally, fluorescence microsocpy demonstrated that physicochemical variations of the fluorophore and linker allowed the subcellular localisation of fluorophores to be modulated, post ligand-receptor intemalisation.

Design, synthesis and characterisation of CCL2 constructs : selective delivery of fluorophores to monocytes

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Design, synthesis and characterisation of CCL2 constructs : selective delivery of fluorophores to monocytes