Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. 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 CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages 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.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

Monocytes and macrophages have crucial and distinct roles in tissue homeostasis and immunity, but they also contribute to a broad spectrum of pathologies and are thus attractive therapeutic targets. Potential intervention strategies that aim to manipulate these cells will require an in-depth understanding of their origins and the mechanisms that ensure their homeostasis. Recent evidence shows that monocytes do not substantially contribute to most tissue macrophage populations in the steady state or during certain types of inflammation. Rather, most tissue macrophage populations in mice are derived from embryonic precursors, are seeded before birth and can maintain themselves in adults by self-renewal. In this Review, we discuss the evidence that has dramatically changed our understanding of monocyte and macrophage development, and the maintenance of these cells in the steady state.

Monocytes and macrophages: developmental pathways and tissue homeostasis

Studies on monocyte and macrophage biology and differentiation have revealed the pleiotropic activities of these cells. Macrophages are tissue sentinels that maintain tissue integrity by eliminating/repairing damaged cells and matrices. In this M2-like mode they can also promote tumor growth. Conversely, M1-like macrophages are key effector cells for the elimination of pathogens, virally infected, and cancer cells. Macrophage differentiation from monocytes occurs in the tissue in concomitance with the acquisition of a functional phenotype that depends on microenvironmental signals, thereby accounting for the many and apparently opposed macrophage functions. Many questions arise. When monocytes differentiate into macrophages in a tissue (concomitantly adopting a specific functional program, M1 or M2), do they all die during the inflammatory reaction, or do some of them survive? Do those that survive become quiescent tissue macrophages, able to react as naive cells to a new challenge? Or, do monocyte-derived tissue macrophages conserve a “memory” of their past inflammatory activation? This review will address some of these important questions under the general framework of the role of monocytes and macrophages in the initiation, development, resolution and chronicization of inflammation.

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From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation

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.

Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny

Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naive, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans.

/pdf/epigenetic-programming-of-monocyte-to-macrophage-1trptw6bu5.pdf

Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity

Minimal Differentiation of Classical Monocytes as They Survey Steady-State Tissues and Transport Antigen to Lymph Nodes

This review updates the basic biology of lung DCs and their functions. Lung DCs have taken center stage as cellular therapeutic targets in new vaccine strategies for the treatment of diverse human disorders, including asthma, allergic lung inflammation, lung cancer, and infectious lung disease. The anatomical distribution of lung DCs, as well as the division of labor between their subsets, aids their ability to recognize and endocytose foreign substances and to process antigens. DCs can induce tolerance in or activate naive T cells, making lung DCs well-suited to their role as lung sentinels. Lung DCs serve as a functional signaling/sensing unit to maintain lung homeostasis and orchestrate host responses to benign and harmful foreign substances.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.0311134

Lung dendritic cells at the innate-adaptive immune interface.

Phagocytic cells such as alveolar macrophages and lung dendritic cells (LDCs) continuously sample antigens from the alveolar spaces in the lungs. LDCs, in particular, are known to migrate to the lung draining lymph nodes (LDLNs) where they present inhaled antigens to T cells initiating an appropriate immune response to a variety of immunogens1,2. To model interactions between the lungs and airborne antigens in mice, antigens can be administered intranasally1,3,4, intratracheally5 or as aerosols6. Delivery by each route involves distinct technical skills and limitations that need to be considered before designing an experiment. For example, intranasal and aerosolized exposure delivers antigens to both the lungs and the upper respiratory tract. Hence antigens can access the nasal associated lymphoid tissue (NALT)7, potentially complicating interpretation of the results. In addition, swallowing, sneezing and the breathing rate of the mouse may also lead to inconsistencies in the doses delivered. Although the involvement of the upper respiratory tract may be preferred for some studies, it can complicate experiments focusing on events specifically initiated in the lungs. In this setting, the intratracheal (i.t) route is preferable as it delivers test materials directly into the lungs and bypasses the NALT. Many i.t injection protocols involve either blind intubation of the trachea through the oral cavity or surgical exposure of the trachea to access the lungs. Herein, we describe a simple, consistent, non-surgical method for i.t instillation. The opening of the trachea is visualized using a laryngoscope and a bent gavage needle is then inserted directly into the trachea to deliver the innoculum. We also describe procedures for harvesting and processing of LDLNs and lungs for analysis of antigen trafficking by flow cytometry.

Tracy Condon

Papers

Minimal Differentiation of Classical Monocytes as They Survey Steady-State Tissues and Transport Antigen to Lymph Nodes

Lung dendritic cells at the innate-adaptive immune interface.

Non-surgical intratracheal instillation of mice with analysis of lungs and lung draining lymph nodes by flow cytometry.

Lung B cells promote early pathogen dissemination and hasten death from inhalation anthrax