Macrophages are distributed in tissues throughout the body and contribute to both homeostasis and disease. Recently, it has become evident that most adult tissue macrophages originate during ...embryonic development and not from circulating monocytes. Each tissue has its own composition of embryonically derived and adult-derived macrophages, but it is unclear whether macrophages of distinct origins are functionally interchangeable or have unique roles at steady state. This new understanding also prompts reconsideration of the function of circulating monocytes. Classical Ly6chi monocytes patrol the extravascular space in resting organs, and Ly6clo nonclassical monocytes patrol the vasculature. Inflammation triggers monocytes to differentiate into macrophages, but whether resident and newly recruited macrophages possess similar functions during inflammation is unclear. Here, we define the tools used for identifying the complex origin of tissue macrophages and discuss the relative contributions of tissue niche versus ontological origin to the regulation of macrophage functions during steady state and inflammation.
It has recently emerged that most adult tissue macrophages originate during embryonic development and not from circulating monocytes. Epelman et al. discuss tools for dissecting the origin of tissue macrophages and examine the contribution of tissue niche versus ontogeny in the regulation of macrophage functions at steady state and during inflammation.
Mononuclear phagocytes (MPs) relevant to atherosclerosis include monocytes, macrophages, and dendritic cells. A decade ago, studies on macrophage behavior in atherosclerotic lesions were often ...limited to quantification of total macrophage area in cross-sections of plaques. Although technological advances are still needed to examine plaque MP populations in an increasingly dynamic and informative manner, innovative methods to interrogate the biology of MPs in atherosclerotic plaques developed in the past few years point to several mechanisms that regulate the accumulation and function of MPs within plaques. Here, I review the evolution of atherosclerotic plaques with respect to changes in the MP compartment from the initiation of plaque to its progression and regression, discussing the roles that recruitment, proliferation, and retention of MPs play at these different disease stages. Additional work in the future will be needed to better distinguish macrophages and dendritic cells in plaque and to address some basic unknowns in the field, including just how cholesterol drives accumulation of macrophages in lesions to build plaques in the first place and how macrophages as major effectors of innate immunity work together with components of the adaptive immune response to drive atherosclerosis. Answers to these questions are sought with the goal in mind of reversing disease where it exists and preventing its development where it does not.
Mammals have two specialized vascular circulatory systems: the blood vasculature and the lymphatic vasculature. The lymphatic vasculature is a unidirectional conduit that returns filtered ...interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays major roles in immune cell trafficking and lipid absorption. As we discuss in this review, the molecular characterization of lymphatic vascular development and our understanding of this vasculature’s role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions. We propose that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body’s response to a wide range of human diseases.
Oliver et al. comprehensively review the anatomy, development, and functional roles of the lymphatic vasculature in health and disease. They highlight emerging evidence suggesting that the lymphatic system plays more diverse physiological roles that previously appreciated.
Monocytes develop in the bone marrow and represent the primary type of mononuclear phagocyte found in the blood. They were long thought of as a source for tissue macrophages, but recent studies ...indicate more complex roles for monocytes, both within the circulation and after their migration into tissues and lymphoid organs. In this Review, we discuss the newer concepts underlying the maturation of emigrating monocytes into different classes of tissue macrophages, as well as their potential functions, as monocyte-derived cells, in the tissues. In addition, we consider the emerging roles for monocytes in adaptive immunity as antigen-presenting cells.
It is thought that monocytes rapidly differentiate to macrophages or dendritic cells (DCs) upon leaving blood. Here we have shown that Ly-6C+ monocytes constitutively trafficked into skin, lung, and ...lymph nodes (LNs). Entry was unaffected in gnotobiotic mice. Monocytes in resting lung and LN had similar gene expression profiles to blood monocytes but elevated transcripts of a limited number of genes including cyclo-oxygenase-2 (COX-2) and major histocompatibility complex class II (MHCII), induced by monocyte interaction with endothelium. Parabiosis, bromodoxyuridine (BrdU) pulse-chase analysis, and intranasal instillation of tracers indicated that instead of contributing to resident macrophages in the lung, recruited endogenous monocytes acquired antigen for carriage to draining LNs, a function redundant with DCs though differentiation to DCs did not occur. Thus, monocytes can enter steady-state nonlymphoid organs and recirculate to LNs without differentiation to macrophages or DCs, revising a long-held view that monocytes become tissue-resident macrophages by default.
•Ly-6C+ not Ly-6C− monocytes enter tissues in the steady state•Tissue monocytes can retain monocyte profile without becoming macrophages or DCs•Tissue monocytes may mediate antigen surveillance: they are MHCII+ and migrate to LNs•MHCII induction on tissue monocytes can be driven by interactions with endothelium
The lymphatic vasculature is not considered a formal part of the immune system, but it is critical to immunity. One of its major roles is in the coordination of the trafficking of antigen and immune ...cells. However, other roles in immunity are emerging. Lymphatic endothelial cells, for example, directly present antigen or express factors that greatly influence the local environment. We cover these topics herein and discuss how other properties of the lymphatic vasculature, such as mechanisms of lymphatic contraction (which immunologists traditionally do not take into account), are nonetheless integral in the immune system. Much is yet unknown, and this nascent subject is ripe for exploration. We argue that to consider the impact of lymphatic biology in any given immunological interaction is a key step toward integrating immunology with organ physiology and ultimately many complex pathologies.
Dendritic cells: The first step Randolph, Gwendalyn J
The Journal of experimental medicine,
03/2021, Letnik:
218, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Ralph M. Steinman's work on dendritic cells began in 1973 when he described and named the cells. Reminiscent of the late Justice Ginsburg's perspective that enduring change happens not suddenly but ...one step at a time, the paper (1973. J. Exp. Med.https://doi.org/10.1084/jem.137.5.1142) was notably the first step in many steps of important work that revealed the nature of dendritic cells.
Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that ...govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1β-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1−/− mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages.
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•Exogenous itaconate exerts anti-inflammatory effects in vitro and in vivo•Itaconate inhibits Sdh and regulates succinate levels in LPS-activated macrophages•Itaconate controls mitochondrial respiration changes in inflammatory macrophages•Itaconate limits IL-1β, IL-18, IL-6, IL-12, NO, and HIF-1α, but not TNF-α, production
Macrophage activation is accompanied by TCA cycle remodeling, resulting in endogenous metabolites moonlighting as regulatory mediators of the inflammatory response. Lampropoulou et al. investigate the role of itaconate, one of the most highly induced metabolites in activated macrophages, and show that itaconate regulates succinate levels, mitochondrial respiration, and cytokine production.
Significance This study addresses a fundamentally important and widely debated issue in the field of inflammation, which is why inflammation can be simultaneously deleterious after injury and yet is ...essential for tissue repair. Recently, an important new paradigm has emerged in the macrophage field: Organs are replete with resident macrophages of embryonic origin, distinct from monocyte-derived macrophages. In this article, we use a new model of cardiac injury and show that distinct macrophage populations derived from embryonic and adult lineages are important determinants of tissue repair and inflammation, respectively. Our data suggest that therapeutics, which inhibit monocyte-derived macrophages and/or selectively harness the function of embryonic-derived macrophages, may serve as novel treatments for heart failure.
The mechanistic basis for why inflammation is simultaneously both deleterious and essential for tissue repair is not fully understood. Recently, a new paradigm has emerged: Organs are replete with resident macrophages of embryonic origin distinct from monocyte-derived macrophages. This added complexity raises the question of whether distinct immune cells drive inflammatory and reparative activities after injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult heart, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition is a key determinant of cardiac tissue repair. Using a genetic model of cardiomyocyte ablation, we demonstrated that neonatal mice expand a population of embryonic-derived resident cardiac macrophages, which generate minimal inflammation and promote cardiac recovery through cardiomyocyte proliferation and angiogenesis. During homeostasis, the adult heart contains embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by monocyte-derived macrophages that are proinflammatory and lacked reparative activities. Inhibition of monocyte recruitment to the adult heart preserved embryonic-derived macrophage subsets, reduced inflammation, and enhanced tissue repair. These findings indicate that embryonic-derived macrophages are key mediators of cardiac recovery and suggest that therapeutics targeting distinct macrophage lineages may serve as novel treatments for heart failure.
GM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103+ DCs in some tissues. Here ...we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103+ and CD11b+ DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8+ T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8+ T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo.
► Csf-2 controls the homeostasis of nonlymphoid tissue-resident DCs in vivo ► Csf-2 receptor is dispensable for the differentiation and function of inflammatory DCs ► Csf-2 promotes the induction of CD8+ T cell immunity through its role on tissue DCs
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