Peripheral blood monocytes are a heterogeneous population of circulating leukocytes. Using a murine adoptive transfer system to probe monocyte homing and differentiation in vivo, we identified two functional subsets among murine blood monocytes: a short-lived CX(3)CR1(lo)CCR2(+)Gr1(+) subset that is actively recruited to inflamed tissues and a CX(3)CR1(hi)CCR2(-)Gr1(-) subset characterized by CX(3)CR1-dependent recruitment to noninflamed tissues. Both subsets have the potential to differentiate into dendritic cells in vivo. The level of CX(3)CR1 expression also defines the two major human monocyte subsets, the CD14(+)CD16(-) and CD14(lo)CD16(+) monocytes, which share phenotype and homing potential with the mouse subsets. These findings raise the potential for novel therapeutic strategies in inflammatory diseases.

Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate, pre-programmed arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses, and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.White blood cells or leukocytes are a diverse group of cell types that mediate the body's immune response. They circulate through the blood and lymphatic system and are recruited to sites of tissue damage and infection. Leukocyte subsets are distinguished by functional and physical characteristics. They have a common origin in hematopoietic stem cells and develop along distinct differentiation pathways in response to internal and external cues. The mononuclear phagocyte system represents a subgroup of leucocytes originally described as a population of bone marrow-derived myeloid cells that circulate in the blood as monocytes and populate tissues as macrophages in the steady state and during inflammation (1). In different tissues they can show significant heterogeneity with respect to phenotype, homeostatic turnover and function. The discovery of dendritic cells (DCs) as a distinct lineage of mononuclear phagocytes, specialized in antigen presentation to T cells and the initiation and control of immunity (2), revealed additional roles of these cells in shaping the immune response to pathogens, vaccines and tumors, as well as additional heterogeneity. Whereas a detailed map of the relationship between monocytes, DCs and their progenitors begins to emerge, other areas like the origin and renewal of tissue macrophage subsets remain less defined. (Fig. 1A) circulate in the blood, bone marrow, and spleen and do not proliferate in a steady state (3,4). Monocytes represent immune effector cells, equipped with chemokine Monocytes

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 CD11bhighmonocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80brightmacrophages 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.

The cellular immune response to tissue damage and infection requires the recruitment of blood leukocytes. This process is mediated through a classical multistep mechanism, which involves transient rolling on the endothelium and recognition of inflammation followed by extravasation. We have shown, by direct examination of blood monocyte functions in vivo, that a subset of monocytes patrols healthy tissues through long-range crawling on the resting endothelium. This patrolling behavior depended on the integrin LFA-1 and the chemokine receptor CX(3)CR1 and was required for rapid tissue invasion at the site of an infection by this "resident" monocyte population, which initiated an early immune response and differentiated into macrophages.