We celebrate the centenary of the Nobel award to Elie Metchnikoff in 2008, shared with Paul Ehrlich, as respective pioneers of cellular and humoral immunology. Metchnikoff is rightly famous for his ...recognition of the biological significance of leukocyte recruitment and phagocytosis of microbes in host defence against infection, inflammation and immunity. As a comparative zoologist he utilised a broad range of model organisms for microscopic studies in vivo and in vitro. His work prefigures much of contemporary research in innate immunity. In this brief review, I cover some details of his Europe-wide life in Russia (mainly Odessa) and at the Pasteur Institute in Paris. He had a complex personality, yet his creative genius, imagination and insights justify the title of "Father of natural immunity".
Macrophages are present in all vertebrate tissues, from mid-gestation throughout life, constituting a widely dispersed organ system. They promote homeostasis by responding to internal and external ...changes within the body, not only as phagocytes in defence against microbes and in clearance of dead and senescent cells, but also through trophic, regulatory and repair functions. In this review, we describe macrophage phenotypic heterogeneity in different tissue environments, drawing particular attention to organ-specific functions.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As the body continues to grow and age, it becomes essential to maintain a balance between living and dying cells. Macrophages and dendritic cells play a central role in discriminating among viable, ...apoptotic, and necrotic cells, as selective and efficient phagocytes, without inducing inappropriate inflammation or immune responses. A great deal has been learnt concerning clearance receptors for modified and non-self-ligands on potential targets, mediating their eventual uptake, disposal, and replacement. In this essay, we assess current understanding of the phagocytic recognition of apoptotic cells within their tissue environment; we conclude that efferocytosis constitutes a more complex process than simply removal of corpses, with regulatory interactions between the target and effector cells, which determine the outcome of this homeostatic process.
The concept of an alternative pathway of macrophage activation has stimulated interest in its definition, mechanism, and functional significance in homeostasis and disease. We assess recent research ...in this field, argue for a restricted definition, and explore pathways by which the T helper 2 (Th2) cell cytokines interleukin-4 (IL-4) and IL-13 mediate their effects on macrophage cell biology, their biosynthesis, and responses to a normal and pathological microenvironment. The stage is now set to gain deeper insights into the role of alternatively activated macrophages in immunobiology.
Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and ...are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response.
Summary
During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious ...stimuli as tissue‐resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation.
It has been a century since the death of Élie Metchnikoff, who championed the role of phagocytosis in cellular immunity. Whereas others had observed the uptake of particles by cells from simple to ...complex organisms, he grasped its significance in the host response to injury and infection and established a firm basis for our understanding of inflammation and tissue homeostasis. The past century has brought improved tools of cellular and molecular biology to the study of phagocytosis and its contribution to physiological and pathological processes, including receptor function in innate and acquired immunity. In this review, I assess our present knowledge and consider opportunities for future research and therapeutic targeting.
Phagocytosis is a cellular process by which specialized leukocytes remove the corpses of dying cells and defend the body against infectious microbes. Siamon Gordon revisits this biological process and places it in the perspective of the phagocyte within its environment.
CD169+ macrophages have fascinated immunologists because of their unique distribution in secondary lymphoid organs, redistribution upon immune activation and, lately, because of their contribution to ...antigen handling. Their association with B cell follicles prompted early studies on their involvement in B cell activation, and recent work has unveiled an unexpected role in facilitating activation of other lymphocyte subsets, such as invariant natural killer T (iNKT) cells. New data also argue that CD169+ macrophages activate CD8 T cells in response to dead cell-associated antigens in lymph nodes and by transferring antigen to dendritic cells (DCs) in the spleen. Understanding the role of CD169+ macrophages in the activation of acquired immunity could benefit the design of vaccination strategies, for example those aimed at eliciting cytotoxic T cells.
We are living through an unprecedented accumulation of data on gene expression by macrophages, reflecting their origin, distribution, and localization within all organs of the body. While the ...extensive heterogeneity of the cells of the mononuclear phagocyte system is evident, the functional significance of their diversity remains incomplete, nor is the mechanism of diversification understood. In this essay we review some of the implications of what we know, and draw attention to issues to be clarified in further research, taking advantage of the powerful genetic, cellular, and molecular tools now available. Our thesis is that macrophage specialization and functions go far beyond immunobiology, while remaining an essential contributor to innate as well as adaptive immunity.
Macrophages are innate immune cells with well-established roles in the primary response to pathogens, but also in tissue homeostasis, coordination of the adaptive immune response, inflammation, ...resolution, and repair. These cells recognize danger signals through receptors capable of inducing specialized activation programs. The classically known macrophage activation is induced by IFN-gamma, which triggers a harsh proinflammatory response that is required to kill intracellular pathogens. Macrophages also undergo alternative activation by IL-4 and IL-13, which trigger a different phenotype that is important for the immune response to parasites. Here we review the cellular sources of these cytokines, receptor signaling pathways, and induced markers and gene signatures. We draw attention to discrepancies found between mouse and human models of alternative activation. The evidence for in vivo alternative activation of macrophages is also analyzed, with nematode infection as prototypic disease. Finally, we revisit the concept of macrophage activation in the context of the immune response.
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