•Tissue-Resident Macrophages are long-lived and derived from embryonic progenitors.•The c-Myb-independent primitive program gives rise to YS Macrophages and Microglia.•The c-Myb-dependent EMPs ...program gives rise to Fetal Monocytes.•The HSCs-definitive program can also give rise to Fetal and Neonatal Monocytes.•Fetal and Neonatal Monocytes give rise to Tissue Macrophages except Microglia.•Adult Monocytes give rise to Tissue-Resident Macrophages under specific conditions.
Tissue-resident macrophages have pivotal functions for tissue defense and homeostasis. Two main discoveries have changed our current understanding of macrophage development: Their embryonic origin and their ability to self-renew throughout the lifespan. It is now well accepted that most tissue-resident macrophages are long-lived cells derived from a transient hematopoietic wave of erythro-myeloid progenitors (EMPs) emerging in the yolk sac. At least two distinct pathways derived from EMPs have been implicated in macrophage development. The first one, c-Myb-independent is giving rise to yolk sac macrophages also called primitive macrophages, and bypassing the classical monocytic intermediates. The second requires c-Myb expression and start once EMPs seed the fetal liver where they generate fetal monocytes. Sequentially, primitive macrophages seed every tissue and will ultimately give rise to microglia in the brain, rapidly isolated by the blood brain barrier, while EMP-derived fetal monocytes infiltrate every other tissues and gradually generate the major pool of adult tissue-resident macrophages by diluting the initial primitive macrophage contribution. A third wave of hematopoietic stem cells (HSC)-derived monocytes is also emerging from the fetal liver to contribute to the long-lived macrophage pool established at birth while the adult hematopoiesis is only starting in the bone marrow. We propose here to review recent insights about the different embryonic hematopoietic programs responsible for the generation of long-lived tissue-resident macrophages and their maintenance after birth.
Resident tissue macrophages (RTMs) have a broad spectrum of immune- and non-immune-related tissue-supporting activities. The roots of this heterogeneity and versatility are only beginning to be ...understood. Here, we propose a conceptual framework for considering the RTM heterogeneity that organizes the factors shaping RTM identity within four cardinal points: (1) ontogeny and the view that adult RTM populations comprise a defined mixture of cells that arise from either embryonic precursors or adult monocytes; (2) local factors unique to the niche of residence, evolving during development and aging; (3) inflammation status; and (4) the cumulative effect of time spent in a specific tissue that contributes to the resilient adaptation of macrophages to their dynamic environment. We review recent findings within this context and discuss the technological advances that are revolutionizing the study of macrophage biology.
Resident tissue macrophages (RTMs) have a broad spectrum of immune- and non-immune-related tissue-supporting activities. Ginhoux and colleagues propose a conceptual framework for considering the RTM heterogeneity that organizes the factors shaping RTM identity within four cardinal points: ontogeny, the niche of residence, inflammation status, and the cumulative effect of time spent in a specific tissue.
Microglia are the resident macrophages of the central nervous system (CNS), which sit in close proximity to neural structures and are intimately involved in brain homeostasis. The microglial ...population also plays fundamental roles during neuronal expansion and differentiation, as well as in the perinatal establishment of synaptic circuits. Any change in the normal brain environment results in microglial activation, which can be detrimental if not appropriately regulated. Aberrant microglial function has been linked to the development of several neurological and psychiatric diseases. However, microglia also possess potent immunoregulatory and regenerative capacities, making them attractive targets for therapeutic manipulation. Such rationale manipulations will, however, require in-depth knowledge of their origins and the molecular mechanisms underlying their homeostasis. Here, we discuss the latest advances in our understanding of the origin, differentiation, and homeostasis of microglial cells and their myelomonocytic relatives in the CNS.
Cross-talk between the nervous and immune systems has been well described in the context of adult physiology and disease. Recent advances in our understanding of immune cell ontogeny have revealed a ...notable interplay between neurons and microglia during the prenatal and postnatal emergence of functional circuits. This Review focuses on the brain, where the early symbiotic relationship between microglia and neuronal cells critically regulates wiring, contributes to sex-specific differences in neural circuits, and relays crucial information from the periphery, including signals derived from the microbiota. These observations underscore the importance of studying neurodevelopment as part of a broader framework that considers nervous system interactions with microglia in a whole-body context.
Resident tissue macrophages (RTMs) are cells with a high functional plasticity assuming pleiotropic roles in their tissue of residence, from clearance of dead cells and metabolic sensing in steady ...state to cytokine production and tissue repair during inflammation. The liver has long been considered as only populated by Kupffer cells (KCs), a macrophage population assumed to be in charge of all of these functions. However, we know now that KCs are not the only macrophage population in the liver, that recently was shown to contain also capsular macrophages, monocyte-derived macrophages as well as recruited peritoneal macrophages inherited from previous inflammatory events. These macrophages exhibit different origins, time of establishing residence and locations in the liver, with both ontogenical and environmental factors shaping their identity and functions. Furthermore, liver macrophages reside in a complex environment with a pronounced metabolic zonation. Here, we briefly discuss how these intrinsic and extrinsic factors influence macrophage biology and liver physiology in general. We notably focus on how the recent advances of single cell transcriptomic approaches are changing our understanding of liver macrophages and diseases.
Dendritic cells (DCs) develop in the bone marrow from haematopoietic progenitors that have numerous shared characteristics between mice and humans. Human counterparts of mouse DC progenitors have ...been identified by their shared transcriptional signatures and developmental potential. New findings continue to revise models of DC ontogeny but it is well accepted that DCs can be divided into two main functional groups. Classical DCs include type 1 and type 2 subsets, which can detect different pathogens, produce specific cytokines and present antigens to polarize mainly naive CD8
or CD4
T cells, respectively. By contrast, the function of plasmacytoid DCs is largely innate and restricted to the detection of viral infections and the production of type I interferon. Here, we discuss genetic models of mouse DC development and function that have aided in correlating ontogeny with function, as well as how these findings can be translated to human DCs and their progenitors.
Microglia are resident macrophages of the central nervous system; they arise during early embryonic development and persist throughout adulthood. These unique cells provide developmental support, ...contribute to adult brain homeostasis and impart immune protection during infection. Dysregulated microglia are implicated in the pathophysiology of several neurological disorders, including Alzheimer disease, and as such, a better understanding of their regulation and function is required for rational therapeutic design. Recent studies have highlighted the various heterogeneous aspects of microglia, such as their wide differentiation spectrum from early embryogenesis to adulthood, their location in different brain regions and their responses to ageing, infection and inflammation. In this review, we discuss microglial heterogeneity in time and space and highlight the remaining questions arising from such heterogeneity.
Main Points
Microglia, CNS resident macrophages, are heterogeneous in their distribution, morphology and functions in development, adulthood and diseases.
Such heterogeneity is controlled by intrinsic factors (sex) or extrinsic factors (niche where they reside).
Highlights • We review the organization and the relationships of mouse and human DC networks. • Mouse and human DC networks are similarly organized. • Mouse CD8α+ /CD103+ DCs are related to human ...CD141+ DCs and excel at crosspresentation. • Mouse CD11b+ DCs are related to human CD1c+ DCs, exhibiting Th17 polarizing properties. • Mouse and human inflammatory DCs exert context-dependent immunity.
Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic ...targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP
fibroblasts and SPP1
macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP
fibroblasts and SPP1
macrophages interaction to improve immunotherapy.
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