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Heart failure (HF) is a frequent consequence of myocardial infarction (MI). Identification of the precise, time-dependent composition of inflammatory cells may provide clues for the establishment of new biomarkers and therapeutic approaches targeting post-MI HF. Here, we investigate the spatiotemporal dynamics of MI-associated immune cells in a mouse model of MI using spatial transcriptomics and single-cell RNA-sequencing (scRNA-seq). We identify twelve major immune cell populations; their proportions dynamically change after MI. Macrophages are the most abundant population at all-time points (>60%), except for day 1 post-MI. Trajectory inference analysis shows upregulation of Trem2 expression in macrophages during the late phase post-MI. In vivo injection of soluble Trem2 leads to significant functional and structural improvements in infarcted hearts. Our data contribute to a better understanding of MI-driven immune responses and further investigation to determine the regulatory factors of the Trem2 signaling pathway will aid the development of novel therapeutic strategies for post-MI HF. Cellular composition and function are not clearly defined in heart failure after myocardial infarction. Here, using single cell and spatial transcriptomics in a MI-HF mouse model, the authors show that macrophages expressing Trem2 are found within the infarcts and this could be a useful biomarker.

Key Points Tumours directly affect mature myeloid cells by converting some of them into immunosuppressive populations that facilitate tumour growth. In cancer, normal myeloid cell differentiation is also diverted from its intrinsic pathway of terminal differentiation to mature myeloid cells (dendritic cells, macrophages and granulocytes) towards a pathway that generates pathologically activated immature cells, which are known as myeloid-derived suppressor cells (MDSCs). MDSCs are immunosuppressive, immature and pathologically activated myeloid cells. However, in the absence of tumour-derived factors, they are still able to differentiate into mature myeloid cells. MDSCs consist of two major populations: polymorphonuclear MDSCs and monocytic MDSCs. MDSCs suppress antigen-specific and nonspecific immune responses through a variety of mechanisms. Myeloid cell responses in cancer are regulated by common tumour-derived factors that activate a diverse set of transcription factors shared by myeloid cells. These transcription factors promote myelopoiesis and initiate the immunosuppressive pathways that commit immature myeloid cells to become MDSCs. A two-stage model of MDSC involvement in tumour development and progression is proposed. A universal feature of tumour progression is the activation of abnormal myelopoiesis and the recruitment of immature myeloid cells into tissues. These cells may or may not possess immunosuppressive features, depending on the activation signals provided by the tumour microenvironment. If immunosuppression is not a property of the first wave of immature myeloid cells that are recruited to tumours, continuous stimulation of myelopoiesis and activation of immature myeloid cells by tumour-derived factors drives the subsequent accumulation of immunosuppressive MDSCs, which support tumour growth and the formation of the metastatic niche. Here, the authors discuss how the immune activities of myeloid cells, such as macrophages and dendritic cells, are affected by the immunosuppressive tumour environment. They propose that tumours can evade the immune system by promoting aberrant differentiation and function of the entire myeloid system. Myeloid cells are the most abundant nucleated haematopoietic cells in the human body and are a collection of distinct cell populations with many diverse functions. The three groups of terminally differentiated myeloid cells — macrophages, dendritic cells and granulocytes — are essential for the normal function of both the innate and adaptive immune systems. Mounting evidence indicates that the tumour microenvironment alters myeloid cells and can convert them into potent immunosuppressive cells. Here, we consider myeloid cells as an intricately connected, complex, single system and we focus on how tumours manipulate the myeloid system to evade the host immune response.

Key Points Liver macrophages comprise Kupffer cells — which are self-maintaining, non-migratory tissue-resident phagocytes that originate from yolk sac-derived precursors during embryogenesis — and monocyte-derived macrophages. Kupffer cells are essential for hepatic and systemic homeostasis, as they contribute to metabolism, scavenge bacteria and cellular debris, and induce immunological tolerance. Following their activation by danger signals, Kupffer cells modulate inflammation and recruit immune cells — including large numbers of monocytes — to the liver. Kupffer cells and monocyte-derived macrophages rapidly adapt their phenotypes in response to local signals, which determine their ability to aggravate or cease liver injury. Liver macrophages are crucial in the pathogenesis of acute and chronic liver diseases, in which they orchestrate inflammation, fibrosis, angiogenesis and tumour progression, as well as tissue repair and tumour surveillance. Evidence from animal models and early clinical trials in humans indicates that targeting pathogenic liver macrophages might be a promising therapeutic approach in acute and chronic liver diseases. This Review describes the different populations of monocytes and macrophages, including Kupffer cells, that are found in the liver. The authors discuss the immune functions of these cells in the homeostatic liver as well as during liver infection and disease. Macrophages represent a key cellular component of the liver, and are essential for maintaining tissue homeostasis and ensuring rapid responses to hepatic injury. Our understanding of liver macrophages has been revolutionized by the delineation of heterogeneous subsets of these cells. Kupffer cells are a self-sustaining, liver-resident population of macrophages and can be distinguished from the monocyte-derived macrophages that rapidly accumulate in the injured liver. Specific environmental signals further determine the polarization and function of hepatic macrophages. These cells promote the restoration of tissue integrity following liver injury or infection, but they can also contribute to the progression of liver diseases, including hepatitis, fibrosis and cancer. In this Review, we highlight novel findings regarding the origin, classification and function of hepatic macrophages, and we discuss their divergent roles in the healthy and diseased liver.

Hematopoietic cells, including lymphoid and myeloid cells, can develop into phenotypically distinct 'subpopulations' with different functions. However, evidence indicates that some of these subpopulations can manifest substantial plasticity (that is, undergo changes in their phenotype and function). Here we focus on the occurrence of phenotypically distinct subpopulations in three lineages of myeloid cells with important roles in innate and acquired immunity: macrophages, mast cells and neutrophils. Cytokine signals, epigenetic modifications and other microenvironmental factors can substantially and, in some cases, rapidly and reversibly alter the phenotype of these cells and influence their function. This suggests that regulation of the phenotype and function of differentiated hematopoietic cells by microenvironmental factors, including those generated during immune responses, represents a common mechanism for modulating innate or adaptive immunity.

The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation. High-burden uptake of apoptotic cells is associated with loss of phagocytosis in resolution phase macrophages. Here, using a transcriptomic analysis of macrophage subsets, we show that non-phagocytic resolution phase macrophages express a distinct IFN-β-related gene signature in mice. We also report elevated levels of IFN-β in peritoneal and broncho-alveolar exudates in mice during the resolution of peritonitis and pneumonia, respectively. Elimination of endogenous IFN-β impairs, whereas treatment with exogenous IFN-β enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. STAT3 signalling in response to IFN-β promotes apoptosis of human PMNs. Finally, uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo. Collectively, these results identify IFN-β produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation. Clearance of apoptotic neutrophils by macrophages is important for the resolution of inflammation. Here, the authors show that interferon-β produced by resolution phase macrophages promotes neutrophil apoptosis and efferocytosis and induces macrophage reprogramming to a pro-resolving phenotype, thereby identifying IFN-β as a multi-pronged pro-resolution cytokine.

Key Points The interplay between transcription factors and epigenetic regulators is crucial for regulating gene-expression programmes during haematopoiesis. Epigenetic regulation — including post-translational modification of histones and DNA methylation — is also linked with upstream signalling pathways and external signals that shape the identity and function of immune cells. Distinctive DNA methylation changes characterize the differentiation of myeloid cells and lymphoid cells from their progenitors. DNA demethylation is more predominant during myeloid differentiation than during lymphoid differentiation. The methylcytosine hydroxylase TET2, which oxidizes 5-methylcytosine, has a major role in the acquisition of myeloid cell identity. This has been demonstrated using transdifferentiation models and is highlighted by the association of TET2 mutations with myeloid malignancies. Epigenetic control has a key role in defining macrophage polarization, connecting external stimuli with the establishment of specific transcriptional programmes. Epigenetic modifications have a key role in the generation of memory-type behaviour in innate immune cells. Following an initial stimulus, the persistence of the trimethylated histone H3K4 at latent enhancers ensures the increased expression of pro-inflammatory genes after restimulation. In this Review, the authors describe the key epigenetic events that are associated with the differentiation and function of cells of the myeloid lineage, with a particular emphasis on monocytes and macrophages. They detail the epigenetic enzymes that control these events and discuss emerging data that show the importance of epigenetic regulation for 'memory-like' behaviour in innate immune cells. Myeloid cells are crucial effectors of the innate immune response and important regulators of adaptive immunity. The differentiation and activation of myeloid cells requires the timely regulation of gene expression; this depends on the interplay of a variety of elements, including transcription factors and epigenetic mechanisms. Epigenetic control involves histone modifications and DNA methylation, and is coupled to lineage-specifying transcription factors, upstream signalling pathways and external factors released in the bone marrow, blood and tissue environments. In this Review, we highlight key epigenetic events controlling myeloid cell biology, focusing on those related to myeloid cell differentiation, the acquisition of myeloid identity and innate immune memory.

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.Genetic models of dendritic cell (DC) development in mice have aided our understanding of the redundant and non-redundant functions of DC subsets and enabled translation of these findings to human DCs.

Cells of the mononuclear phagocyte system (MPS) are usually defined by particular functional or phenotypical characteristics. However, this has led to confusion in the field, as many of the criteria that are used to define a particular cell population may actually be shared with other cell types. In this Opinion article, the authors propose that a new nomenclature that is based on cell ontogeny could enable a more robust classification of MPS cells. The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. However, considering that these characteristics are often overlapping, the distinction between and classification of these cell types has been challenging. In this Opinion article, we propose a unified nomenclature for the MPS. We suggest that these cells can be classified primarily by their ontogeny and secondarily by their location, function and phenotype. We believe that this system permits a more robust classification during both steady-state and inflammatory conditions, with the benefit of spanning different tissues and across species.