Tissue-resident macrophages: guardians of organ homeostasis.
Nobs Samuel Philip,Kopf Manfred
Trends in immunology
Tissue-resident macrophages (M) have recently emerged as a key rheostat capable of regulating the balance between organ health and disease. In most organs, ontogenetically and functionally distinct macrophage subsets fulfill a plethora of functions specific to their tissue environment. In this review, we summarize recent findings regarding the ontogeny and functions of macrophage populations in different mammalian tissues, describing how these cells regulate tissue homeostasis and how they can contribute to inflammation. Furthermore, we highlight new developments concerning certain general principles of tissue macrophage biology, including the importance of metabolism for understanding macrophage activation states and the influence of intrinsic and extrinsic factors on macrophage metabolic control. We also shed light on certain open questions in the field and how answering these might pave the way for tissue-specific therapeutic approaches.
10.1016/j.it.2021.04.007
Reframing macrophage diversity with network motifs.
Trends in immunology
A binary classification of macrophage activation as inflammatory or resolving does not capture the diversity of macrophage states observed in tissues. However, framing macrophage activation as a continuous spectrum of states overlooks the intracellular and extracellular networks that regulate and coordinate macrophage responses. Here, we suggest that the systems biology concept of network motifs, which incorporate rules of local molecular interactions, is useful for reframing macrophage activation. Because network motifs can be used to regulate distinct biological functions, they offer a simplified unit that can be compared across organismal, tissue, and disease contexts. Moreover, defining macrophage states as combinations of functional modules regulated by network motifs offers a framework to ultimately predict and target macrophage responses arising in complex environments.
10.1016/j.it.2023.10.009
Metabolic adaptations of tissue-resident immune cells.
Caputa George,Castoldi Angela,Pearce Edward J
Nature immunology
Unlike other cells in the body, immune cells have to be able to enter and adapt to life within diverse tissues. Immune cells develop within dedicated immune system organs, such as the bone marrow, thymus and lymphoid tissues, but also inhabit other tissues, wherein they not only provide defense against infection and malignancies but also contribute to homeostatic tissue function. Because different tissues have widely divergent metabolic rates and fuel requirements, this raises interesting questions about the adaptation of immune cells in specific tissues. When immune cells take up residence in different tissues, they develop a transcriptional signature that reflects adaptation to life and function within that tissue. Genes encoding metabolic-pathway proteins are strongly represented within these signatures, reflective of the importance of metabolic adaptation to tissue residence. In this Review, we discuss the available data on the metabolic adaptation of immune cells to life in different tissue sites, within the broader framework of how functional adaptation versus maladaptation in the niche can affect tissue homeostasis.
10.1038/s41590-019-0407-0
Macrophage states: there's a method in the madness.
Trends in immunology
Single-cell approaches have shone a spotlight on discrete context-specific tissue macrophage states, deconstructed to their most minute details. Machine-learning (ML) approaches have recently challenged that dogma by revealing a context-agnostic continuum of states shared across tissues. Both approaches agree that 'brake' and 'accelerator' macrophage subpopulations must be balanced to achieve homeostasis. Both approaches also highlight the importance of ensemble fluidity as subpopulations switch between wide ranges of accelerator and brake phenotypes to mount the most optimal wholistic response to any threat. A full comprehension of the rules that govern these brake and accelerator states is a promising avenue because it can help formulate precise macrophage re-education therapeutic strategies that might selectively boost or suppress disease-associated states and phenotypes across various tissues.
10.1016/j.it.2023.10.006
Macrophage heterogeneity in the single-cell era: facts and artifacts.
Blood
In this spotlight, we review technical issues that compromise single-cell analysis of tissue macrophages, including limited and unrepresentative yields, fragmentation and generation of remnants, and activation during tissue disaggregation. These issues may lead to a misleading definition of subpopulations of macrophages and the expression of macrophage-specific transcripts by unrelated cells. Recognition of the technical limitations of single-cell approaches is required in order to map the full spectrum of tissue-resident macrophage heterogeneity and assess its biological significance.
10.1182/blood.2023020597
Functional Hallmarks of Healthy Macrophage Responses: Their Regulatory Basis and Disease Relevance.
Annual review of immunology
Macrophages are first responders for the immune system. In this role, they have both effector functions for neutralizing pathogens and sentinel functions for alerting other immune cells of diverse pathologic threats, thereby initiating and coordinating a multipronged immune response. Macrophages are distributed throughout the body-they circulate in the blood, line the mucosal membranes, reside within organs, and survey the connective tissue. Several reviews have summarized their diverse roles in different physiological scenarios and in the initiation or amplification of different pathologies. In this review, we propose that both the effector and the sentinel functions of healthy macrophages rely on three hallmark properties: response specificity, context dependence, and stimulus memory. When these hallmark properties are diminished, the macrophage's biological functions are impaired, which in turn results in increased risk for immune dysregulation, manifested by immune deficiency or autoimmunity. We review the evidence and the molecular mechanisms supporting these functional hallmarks.
10.1146/annurev-immunol-101320-031555
Diversity, Mechanisms, and Significance of Macrophage Plasticity.
Annual review of pathology
Macrophages are a diverse set of cells present in all body compartments. This diversity is imprinted by their ontogenetic origin (embryonal versus adult bone marrow-derived cells); the organ context; by their activation or deactivation by various signals in the contexts of microbial invasion, tissue damage, and metabolic derangement; and by polarization of adaptive T cell responses. Classic adaptive responses of macrophages include tolerance, priming, and a wide spectrum of activation states, including M1, M2, or M2-like. Moreover, macrophages can retain long-term imprinting of microbial encounters (trained innate immunity). Single-cell analysis of mononuclear phagocytes in health and disease has added a new dimension to our understanding of the diversity of macrophage differentiation and activation. Epigenetic landscapes, transcription factors, and microRNA networks underlie the adaptability of macrophages to different environmental cues. Macrophage plasticity, an essential component of chronic inflammation, and its involvement in diverse human diseases, most notably cancer, is discussed here as a paradigm.
10.1146/annurev-pathmechdis-012418-012718