In many mammalian tissues, mature differentiated cells are replaced by self-renewing stem cells, either continuously during homeostasis or in response to challenge and injury. For example, ...hematopoietic stem cells generate all mature blood cells, including monocytes, which have long been thought to be the major source of tissue macrophages. Recently, however, major macrophage populations were found to be derived from embryonic progenitors and to renew independently of hematopoietic stem cells. This process may not require progenitors, as mature macrophages can proliferate in response to specific stimuli indefinitely and without transformation or loss of functional differentiation. These findings suggest that macrophages are mature differentiated cells that may have a self-renewal potential similar to that of stem cells.
Monocytes are circulating blood leukocytes that play important roles in the inflammatory response, which is essential for the innate response to pathogens. But inflammation and monocytes are also ...involved in the pathogenesis of inflammatory diseases, including atherosclerosis. In adult mice, monocytes originate in the bone marrow in a Csf-1R (MCSF-R, CD115)-dependent manner from a hematopoietic precursor common for monocytes and several subsets of macrophages and dendritic cells (DCs). Monocyte heterogeneity has long been recognized, but in recent years investigators have identified three functional subsets of human monocytes and two subsets of mouse monocytes that exert specific roles in homeostasis and inflammation in vivo, reminiscent of those of the previously described classically and alternatively activated macrophages. Functional characterization of monocytes is in progress in humans and rodents and will provide a better understanding of the pathophysiology of inflammation.
Tissue macrophage identity and self-renewal Gentek, Rebecca; Molawi, Kaaweh; Sieweke, Michael H.
Immunological reviews,
November 2014, Letnik:
262, Številka:
1
Journal Article
Recenzirano
Summary
Macrophages are cellular components of the innate immune system that reside in virtually all tissues and contribute to immunity, repair, and homeostasis. The traditional view that all ...tissue‐resident macrophages derive from the bone marrow through circulating monocyte intermediates has dramatically shifted recently with the observation that macrophages from embryonic progenitors can persist into adulthood and self‐maintain by local proliferation. In several tissues, however, monocytes also contribute to the resident macrophage population, on which the local environment can impose tissue‐specific macrophage functions. These observations have raised important questions: What determines resident macrophage identity and function, ontogeny or environment? How is macrophage proliferation regulated? In this review, we summarize the current knowledge about the identity, proliferation, and turnover of tissue‐resident macrophages and how they differ from freshly recruited short‐lived monocyte‐derived cells. We examine whether macrophage proliferation can be qualified as self‐renewal of mature differentiated cells and whether the concepts and molecular pathways are comparable to self‐renewal mechanisms in stem cells. Finally, we discuss how improved understanding of macrophage identity and self‐renewal could be exploited for therapeutic intervention of macrophage‐mediated pathologies by selectively targeting freshly recruited or resident macrophages.
Experimental and clinical evidence suggests that tumor-associated macrophages (TAMs) play important roles in cancer progression. Here, we have characterized the ontogeny and function of TAM subsets ...in a mouse model of metastatic ovarian cancer that is representative for visceral peritoneal metastasis. We show that the omentum is a critical premetastatic niche for development of invasive disease in this model and define a unique subset of CD163+ Tim4+ resident omental macrophages responsible for metastatic spread of ovarian cancer cells. Transcriptomic analysis showed that resident CD163+ Tim4+ omental macrophages were phenotypically distinct and maintained their resident identity during tumor growth. Selective depletion of CD163+ Tim4+ macrophages in omentum using genetic and pharmacological tools prevented tumor progression and metastatic spread of disease. These studies describe a specific role for tissue-resident macrophages in the invasive progression of metastatic ovarian cancer. The molecular pathways of cross-talk between tissue-resident macrophages and disseminated cancer cells may represent new targets to prevent metastasis and disease recurrence.
Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate 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.
Testicular macrophages (tMφ) are the principal immune cells of the mammalian testis. Beyond classical immune functions, they have been shown to be important for organogenesis, spermatogenesis, and ...male hormone production. In the adult testis, two different macrophage populations have been identified based on their distinct tissue localization and morphology, but their developmental origin and mode of homeostatic maintenance are unknown. In this study, we use genetic lineage-tracing models and adoptive transfer protocols to address this question. We show that embryonic progenitors give rise to the interstitial macrophage population, whereas peritubular macrophages are exclusively seeded postnatally in the prepuberty period from bone marrow (BM)-derived progenitors. As the proliferative capacity of interstitial macrophages declines, BM progenitors also contribute to this population. Once established, both the peritubular and interstitial macrophage populations exhibit a long life span and a low turnover in the steady state. Our observations identify distinct developmental pathways for two different tMφ populations that have important implications for the further dissection of their distinct roles in organ homeostasis and testicular function.
Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during ...brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain--early, pre-, and adult microglia--which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.
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Macrophages are innate immune cells present in essentially every organ of the body with dedicated tissue specific functions. We will present in this review the unique properties and ...functions of macrophage populations residing in the testis, an immune-privileged organ. Testicular macrophages (tMΦ) could be seen as guardians of fertility due to their immunosuppressive functions protecting spermatogenesis from auto immune-attack. They exhibit testis specific functions with essential roles in normal testis homeostasis and fetal testicular development. Recently, two distinct testicular macrophage populations have been characterized based on different localization, morphology, gene expression profiles, developmental origin and postnatal development. We will discuss the importance of these two testicular macrophage populations for organ specific functions such as testosterone production and spermatogenesis, as well as their role in establishing immuno-privilege highlighting the contributions of macrophages to male fertility.
Tissues in multicellular organisms are populated by resident macrophages, which perform both generic and tissue‐specific functions. The latter are induced by signals from the microenvironment and ...rely on unique tissue‐specific molecular programs requiring the combinatorial action of tissue‐specific and broadly expressed transcriptional regulators. Here, we identify the transcription factors Bhlhe40 and Bhlhe41 as novel regulators of alveolar macrophages (AMs)—a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AMs exhibited decreased proliferation that resulted in a severe disadvantage of knockout AMs in a competitive setting. Gene expression analyses revealed a broad cell‐intrinsic footprint of Bhlhe40/Bhlhe41 deficiency manifested by a downregulation of AM signature genes and induction of signature genes of other macrophage lineages. Genome‐wide characterization of Bhlhe40 DNA binding suggested that these transcription factors directly repress the expression of lineage‐inappropriate genes in AMs. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self‐renewal and guardians of their identity.
Synopsis
Tissue‐specific macrophage programs are controlled by the combinatorial action of tissue‐specific and broadly expressed transcriptional regulators. The newly identified Bhlhe40 and Bhlhe41 transcription factors safeguard alveolar macrophage identity and self‐renewal by repressing “lineage‐inappropriate” genes.
Bhlhe40 and Bhlhe41 are required for competitive fitness of alveolar macrophages.
Bhlhe40/Bhlhe41‐deficient alveolar macrophages exhibit decreased proliferation associated with upregulation of Maf and Mafb, which negatively regulate macrophage proliferation.
Genes normally expressed in other tissue‐resident macrophages are upregulated in Bhlhe40/Bhlhe41‐deficient alveolar macrophages.
Bhlhe40 binds to the regulatory elements of many of these genes, and, together with Bhlhe41, limits H3K27 acetylation at these regions.
Two newly identified transcription factors safeguard identity and self‐renewal of tissue‐specific macrophages in lung alveoli via repression of “lineage‐inappropriate” genes.
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