Self-maintaining resident macrophages populate all mammalian organs. In addition to their role as immune sentinels, macrophages perform day-to-day functions essential to tissue homeostasis. The ...homeostatic functions of macrophages are regulated by so-called tissular “niches” that control the size of the macrophage population and imprint their tissue-specific identity. Here, we review the mechanisms underlying self-maintenance of distinct macrophage populations and outline the organizing principles of the macrophage niche. We examine recent studies that uncovered mutually beneficial cell-cell circuits established between macrophages and their niche and propose a modular view of tissues that integrates the resident macrophage as an essential component of each individual module. Manipulating macrophage niche cells to control the function of resident macrophages in vivo might have therapeutic value in various disease settings.
Guilliams et al. review the mechanisms underlying self-maintenance of the distinct resident macrophage populations and outline the organizing principles of the macrophage niche. In the context of evidence for the existence of mutually beneficial cell-cell circuits between macrophage and niche cells, the authors propose a modular view of tissues that integrates the resident macrophage as an essential component.
•Pre-macrophages share a core program established by lineage-determining transcription factors.•Signal-dependent transcription factors adapt the core program.•Niche signals instruct pre-macrophages ...to perform tissue-specific functions.•One organ may contain multiple niches and different organs may contain similar niches.
Tissue-resident macrophages form an essential part of the first line of defense in all tissues of the body. Next to their immunological role, they play an important role in maintaining tissue homeostasis. Recently, it was shown that they are primarily of embryonic origin. During embryogenesis, precursors originating in the yolk sac and fetal liver colonize the embryonal tissues where they develop into mature tissue-resident macrophages. Their development is governed by two distinct sets of transcription factors. First, in the pre-macrophage stage, a core macrophage program is established by lineage-determining transcription factors. Under the influence of tissue-specific signals, this core program is refined by signal-dependent transcription factors. This nurturing by the niche allows the macrophages to perform tissue-specific functions. In the last 15 years, some of these niche signals and transcription factors have been identified. However, detailed insight in the exact mechanism of development is still lacking.
The liver is the largest solid organ in the body, yet it remains incompletely characterized. Here we present a spatial proteogenomic atlas of the healthy and obese human and murine liver combining ...single-cell CITE-seq, single-nuclei sequencing, spatial transcriptomics, and spatial proteomics. By integrating these multi-omic datasets, we provide validated strategies to reliably discriminate and localize all hepatic cells, including a population of lipid-associated macrophages (LAMs) at the bile ducts. We then align this atlas across seven species, revealing the conserved program of bona fide Kupffer cells and LAMs. We also uncover the respective spatially resolved cellular niches of these macrophages and the microenvironmental circuits driving their unique transcriptomic identities. We demonstrate that LAMs are induced by local lipid exposure, leading to their induction in steatotic regions of the murine and human liver, while Kupffer cell development crucially depends on their cross-talk with hepatic stellate cells via the evolutionarily conserved ALK1-BMP9/10 axis.
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•Spatial proteogenomic single-cell atlas of healthy and obese murine and human liver•Validated flow cytometry and microscopy panels for all hepatic cells•LAMs are differentially located in the lean and obese liver•Evolutionary conserved BMP9/10-ALK1 axis is essential for KC development
By combining single-cell and -nucleus sequencing with spatial mapping of RNA and proteins, this vast spatial proteogenomic atlas of healthy and obese human and mouse livers presents methods to identify and localize all hepatic cells and provides insights into hepatic myeloid cells, including identification of reliable surface markers for isolation and localization of hepatic macrophages, characterization of lipid-associated macrophages in both healthy and steatotic livers, determination of a key regulatory axis of Kupffer cell development, and identification of a conserved core gene expression signature of Kupffer cells across 7 species, including chickens and zebrafish.
Self-renewing tissue-resident macrophages are thought to be exclusively derived from embryonic progenitors. However, whether circulating monocytes can also give rise to such macrophages has not been ...formally investigated. Here we use a new model of diphtheria toxin-mediated depletion of liver-resident Kupffer cells to generate niche availability and show that circulating monocytes engraft in the liver, gradually adopt the transcriptional profile of their depleted counterparts and become long-lived self-renewing cells. Underlining the physiological relevance of our findings, circulating monocytes also contribute to the expanding pool of macrophages in the liver shortly after birth, when macrophage niches become available during normal organ growth. Thus, like embryonic precursors, monocytes can and do give rise to self-renewing tissue-resident macrophages if the niche is available to them.
The phenotypic and functional dichotomy between IRF8+ type 1 and IRF4+ type 2 conventional dendritic cells (cDC1s and cDC2s, respectively) is well accepted; it is unknown how robust this dichotomy is ...under inflammatory conditions, when additionally monocyte-derived cells (MCs) become competent antigen-presenting cells (APCs). Using single-cell technologies in models of respiratory viral infection, we found that lung cDC2s acquired expression of the Fc receptor CD64 shared with MCs and of IRF8 shared with cDC1s. These inflammatory cDC2s (inf-cDC2s) were superior in inducing CD4+ T helper (Th) cell polarization while simultaneously presenting antigen to CD8+ T cells. When carefully separated from inf-cDC2s, MCs lacked APC function. Inf-cDC2s matured in response to cell-intrinsic Toll-like receptor and type 1 interferon receptor signaling, upregulated an IRF8-dependent maturation module, and acquired antigens via convalescent serum and Fc receptors. Because hybrid inf-cDC2s are easily confused with monocyte-derived cells, their existence could explain why APC functions have been attributed to MCs.
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•Type I interferon drives differentiation of inf-cDC2s that closely resemble MCs•Inf-cDC2s prime CD4+ and CD8+ T cells, whereas MCs lack APC function•Inf-cDC2s internalize antibody-complexed antigen via Fc receptors•IRF8 controls maturation gene module in inf-cDC2s
The dichotomy between type 1 and 2 conventional DCs under steady-state conditions is well defined. Bosteels et al. demonstrate that, upon inflammation, cDC2s acquire a hybrid inf-cDC2 phenotype, sharing phenotype, gene expression, and function with cDC1s and monocyte-derived cells, to optimally boost CD4 and CD8 immunity via Fc receptors.
While the roles of parenchymal microglia in brain homeostasis and disease are fairly clear, other brain-resident myeloid cells remain less well understood. By dissecting border regions and combining ...single-cell RNA-sequencing with high-dimensional cytometry, bulk RNA-sequencing, fate-mapping and microscopy, we reveal the diversity of non-parenchymal brain macrophages. Border-associated macrophages (BAMs) residing in the dura mater, subdural meninges and choroid plexus consisted of distinct subsets with tissue-specific transcriptional signatures, and their cellular composition changed during postnatal development. BAMs exhibited a mixed ontogeny, and subsets displayed distinct self-renewal capacity following depletion and repopulation. Single-cell and fate-mapping analysis both suggested that there is a unique microglial subset residing on the apical surface of the choroid plexus epithelium. Finally, gene network analysis and conditional deletion revealed IRF8 as a master regulator that drives the maturation and diversity of brain macrophages. Our results provide a framework for understanding host-macrophage interactions in both the healthy and diseased brain.
In the skin, the lack of markers permitting the unambiguous identification of macrophages and of conventional and monocyte-derived dendritic cells (DCs) complicates understanding of their ...contribution to skin integrity and to immune responses. By combining CD64 and CCR2 staining, we successfully identified each of these cell types and studied their origin, transcriptomic signatures, and migratory and T cell stimulatory properties. We also analyzed the impact of microbiota on their development and their contribution to skin inflammation during contact hypersensitivity. Dermal macrophages had a unique scavenging role and were unable to migrate and activate T cells. Conventional dermal DCs excelled both at migrating and activating T cells. In the steady-state dermis, monocyte-derived DCs are continuously generated by extravasated Ly-6Chi monocytes. Their T cell stimulatory capacity combined with their poor migratory ability made them particularly suited to activate skin-tropic T cells. Therefore, a high degree of functional specialization occurs among the mononuclear phagocytes of the skin.
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•CD64 and CCR2 expression permits to resolve skin mononuclear phagocyte complexity•Ly-6Chi monocytes enter healthy dermis and continuously generate monocyte-derived DCs•Monocyte-derived DCs have reduced T cell stimulatory capacity compared to dermal DCs•Dermal macrophages are of dual origin and unable to migrate and activate T cells
Macrophages are highly heterogeneous tissue-resident immune cells that perform a variety of tissue-supportive functions. The current paradigm dictates that intestinal macrophages are continuously ...replaced by incoming monocytes that acquire a pro-inflammatory or tissue-protective signature. Here, we identify a self-maintaining population of macrophages that arise from both embryonic precursors and adult bone marrow-derived monocytes and persists throughout adulthood. Gene expression and imaging studies of self-maintaining macrophages revealed distinct transcriptional profiles that reflect their unique localization (i.e., closely positioned to blood vessels, submucosal and myenteric plexus, Paneth cells, and Peyer’s patches). Depletion of self-maintaining macrophages resulted in morphological abnormalities in the submucosal vasculature and loss of enteric neurons, leading to vascular leakage, impaired secretion, and reduced intestinal motility. These results provide critical insights in intestinal macrophage heterogeneity and demonstrate the strategic role of self-maintaining macrophages in gut homeostasis and intestinal physiology.
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•Self-maintaining macrophages (gMacs) colonize distinct niches of the gut•gMacs have a unique transcriptional profile depending on the niche in which they reside•gMacs support enteric neurons and submucosal vasculature•Loss of gMacs results in vascular leakage, reduced intestinal secretion, and transit
A population of self-maintaining macrophages that persists throughout adulthood promotes intestinal homeostasis, contrary to the idea that short-lived monocytes perform this function.
Defining the origins and developmental pathways of tissue-resident macrophages should help refine our understanding of the role of these cells in various disease settings and enable the design of ...novel macrophage-targeted therapies. In recent years the long-held belief that macrophage populations in the adult are continuously replenished by monocytes from the bone marrow (BM) has been overturned with the advent of new techniques to dissect cellular ontogeny. The new paradigm suggests that several tissue-resident macrophage populations are seeded during waves of embryonic hematopoiesis and self-maintain independently of BM contribution during adulthood. However, the exact nature of the embryonic progenitors that give rise to adult tissue-resident macrophages is still debated, and the mechanisms enabling macrophage population maintenance in the adult are undefined. Here, we review the emergence of these concepts and discuss current controversies and future directions in macrophage biology.
Recent advances revealed that tissue-resident macrophages can have multiple cellular origins deriving from both adult and embryonic progenitors depending of the tissue in which they reside. Ginhoux and Guilliams review these advances and discuss the different proposed models of macrophage ontogeny.
Glioblastomas are aggressive primary brain cancers that recur as therapy-resistant tumors. Myeloid cells control glioblastoma malignancy, but their dynamics during disease progression remain poorly ...understood. Here, we employed single-cell RNA sequencing and CITE-seq to map the glioblastoma immune landscape in mouse tumors and in patients with newly diagnosed disease or recurrence. This revealed a large and diverse myeloid compartment, with dendritic cell and macrophage populations that were conserved across species and dynamic across disease stages. Tumor-associated macrophages (TAMs) consisted of microglia- or monocyte-derived populations, with both exhibiting additional heterogeneity, including subsets with conserved lipid and hypoxic signatures. Microglia- and monocyte-derived TAMs were self-renewing populations that competed for space and could be depleted via CSF1R blockade. Microglia-derived TAMs were predominant in newly diagnosed tumors, but were outnumbered by monocyte-derived TAMs following recurrence, especially in hypoxic tumor environments. Our results unravel the glioblastoma myeloid landscape and provide a framework for future therapeutic interventions.
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