A number of cells of both populations probably die during inflammation, the extent of their survival possibly depending on the nature and magnitude of the insult.
Generally, the inflammatory monocyte-derived macrophages are polarized toward M1, and the majority of them dies, killed by their own NO production see above. In an experimental acute lung injury model, these cells undergo Fas-mediated death, while the resident alveolar cells persist From that, we can argue that M1 likely is a terminal differentiation phenotype.
However, there are reports that they can also undergo in situ phenotype conversation to become tissue-resident macrophages either during inflammation or after experimental deletion of tissue macrophages 48 , This underlines the notion that macrophage polarization is both transient and plastic.
The survival in the tissue of inflammatory monocyte-derived macrophages raises important questions that need to be answered. And, do tissue macrophages resume their previous functional phenotype in response to a new inflammatory challenge? Their fate in the tissue is, however, unknown, since no long-term experiments have been performed in mammals. It is possible that a part of them dies after reacting to a new inflammatory challenge.
If some of them survive again, this possibly depends on the type and magnitude of the new challenge , they would probably behave like inflammatory monocyte-derived macrophages, i. Another population that should be considered is that of monocytes recruited from the blood during the post-inflammatory phase. Recently, this phenomenon has been re-named trained innate immunity Innate memory plays an important defensive role in organisms lacking adaptive immunity, such as plants and invertebrates, but it is evident also in vertebrates lacking functional T and B lymphocytes In these animals, this innate memory mechanism was shown to involve innate immune cells with low turnover [such as macrophages and NK cells; , ] that would be responsible for improved pathogen recognition through pathogen recognition receptors, and for an enhanced protective inflammatory response , NK cells could generate a memory response to viruses, while macrophages retain memory of both bacterial and viral challenges.
A logical possibility is that the microorganisms encountered by the host on a regular basis may serve to differentiating and continually renewing a pool of memory-like macrophages with enhanced reactivity to infectious challenges.
The molecular mechanisms responsible for shifting macrophages toward a memory status have not yet been elucidated. Establishment of macrophage memory, depending on the experienced challenges, is likely to rely on epigenetic changes, as these can be at the basis of a rapid evolution of responsiveness and adaptation to incurring events, thereby allowing to surviving to new environmental threats , Efficacy of many vaccines probably implies the induction of non-specific macrophage memory that contributes to the increased resistance to infections.
Research in the field of memory macrophages needs a thorough re-assessment of a large body of old evidence accumulated in the past decades in the areas of macrophage activation and of adjuvanticity. The notion of innate memory , an old concept that has been recently revived with the description of the so-called trained innate immunity. Thus, new knowledge on macrophage biology and functions will have a direct impact on our understanding of immune responses and on the design of novel therapeutic strategies.
For this reason, it is necessary to overcome several experimental obstacles that delay the full understanding of the new dynamics and relationships within the immune system, and that have been identified by the researchers cited in the review.
For example, to date, transcriptome analysis of monocyte subsets has been done at the basal unstimulated level, showing dramatic differences consistent with a different functional repertoire for the three types of human monocytes. Thus, the true role of the different monocyte subsets could be only understood after activation, and the stimulus-induced transcriptome of these cells will be required. This obviously cannot provide reliable information on the long-term capacity of macrophage self-renewal.
Precautions need to be taken when drastic experimental procedures such as monocyte depletion or parabiosis are used to study macrophages self-renewal. These treatments can alter the concentration of circulating CSF-1 and CSFR1 signaling, which are important for self-renewal of resident macrophages under homeostatic conditions, and critical for differentiation of monocytes into tissue macrophages.
Thus, the lack of recruitment of monocytes from the blood to the tissue could be due to lack of release of monocytes from bone marrow to the blood, where circulating monocytes are decreased. Our final recommendation, therefore, is probably obvious, but it is anyway important to state it again. We need to re-evaluate patiently and critically a huge body of experimental evidence that is already present in the literature.
In particular, we need to overcome the lack of consensus in defining and describing the different macrophage phenotypes Many old studies have already generated information that, in light of our present knowledge, can become very important and help us to clarify the general picture.
Second recommendation is that of designing experiments very carefully, keeping in mind that the immune system is redundant and that the same factor can have different activities, and that the same activity can be carried out by different factors. Third recommendation: monocytes and macrophages are never isolated in the body, and what they do and what they become are totally influenced by the surrounding cells and tissue.
In vitro systems may only partially reproduce this complexity. Last recommendation: consider evolution as an incommensurable and most precious source of information that can greatly help us understand the ontology and behavior of monocytes and macrophages.
Common mechanisms are many, and also species-specific differences exist, thus we should be able to pick up the relevant common information without, however, forgetting that human being is not a mouse or a mosquito.
Paola Italiani wrote the paper; Diana Boraschi contributed to writing and critically revised the paper. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors wish to thank Dr. Charles Mills for helpful discussion and for his continuous assistance in writing this review. Matzinger P. Friendly and dangerous signals: is the tissue in control?
Nat Immunol 8 —3. Medzhitov R. Origin and physiological roles of inflammation. Nature — Nathan C. Points of control in inflammation. The origin and kinetics of mononuclear phagocytes. J Exp Med — Taylor PR, Gordon S. Monocytes heterogeneity and innate immunity. Immunity 19 :2—4.
Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science — Blood — Unravelling mononuclear phagocyte heterogeneity.
Nat Rev Immunol 10 — Homeostasis in the mononuclear phagocyte system. Trends Immunol 35 — Development of monocytes, macrophages, and dendritic cells. Boltjes A, van Wijk F. Human dendritic cell functional specialization in steady-state and inflammation. Front Immunol 5 A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Beyond stem cells: self-renewal of differentiated macrophages.
Science Mills CD, Ley K. M1 and M2 macrophages: the chicken and the egg of immunity. J Innate Immun 6 6. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature —7. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science —7. Origin of monocytes and macrophages in a committed progenitor.
Nat Immunol 14 — In vivo analysis of dendritic cell development and homeostasis. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.
Nat Neurosci 10 — Hamilton JA. Colony-stimulating factor in inflammation and autoimmunity. Nat Rev Immunol 8 — Macrophages specifically regulate the concentration of their own growth factor in the circulation. Survival of mononuclear phagocytes depends on a lineage-specific growth factor that the differentiated cells selectively destroy. Cell 28 — Structure 20 — Nat Immunol 13 — Burgess AW, Metcalf D.
The nature and action of granulocyte-macrophage colony stimulating factors. Blood 56 — Gasson J. Molecular physiology of granulocyte-macrophage colony stimulating factor.
Blood 77 — Google Scholar. Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26 — In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses. On-site education of VEGF-recruited monocytes improves their performance as angiogenic and arteriogenic accessory cells.
Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood 74 — Nomenclature of monocytes and dendritic cells in blood.
Blood :e74— Genetic evidence of a functional monocyte dichotomy. Inflammation 30 — Identification of novel functional differences in monocyte subsets using proteomic and transcriptomic methods. J Proteome Res 8 — BMC Genomics 10 Immunity 33 — Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood :e16— Blood :e50— Transcript profiling of CDpositive monocytes reveals a unique molecular fingerprint. Eur J Immunol 42 — Experimental comparison and cross-validation of the Affymetrix and Illumina gene expression analysis platforms.
Nucleic Acids Res 33 — Toward a refined definition of monocyte subsets. Front Immunol 4 The three human monocyte subsets: implications for health and disease. Immunol Res 53 — Comparison of gene expression profiles between human and mouse monocyte subsets. Blood :e10—9. Blood monocytes consist of two principal subsets with distinct migratory properties.
Immunity 19 — J Clin Invest —9. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Ziegler-Heitbrock L. Reprint of: monocyte subsets in man and other species. Cell Immunol Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response.
J Immunol —7. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38 — Monocytes give rise to mucosal, but not splenic, conventional dendritic cells. An antibody against the colony-stimulating factor 1 receptor depletes the resident subset of monocytes and tissue- and tumor-associated macrophages but does not inhibit inflammation. Nr4a1-dependent Ly6C low monocytes monitor endothelial cells and orchestrate their disposal.
Cell — Nat Immunol 12 — Tissue LyC6- macrophages are generated in the absence of circulating LyC6- monocytes and Nur77 in a model of muscle regeneration. J Immunol — Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol 11 — Identification of splenic reservoir monocytes and their deployment to inflammatory sites.
Science —6. Circadian gene Bmal1 regulates diurnal oscillations of Ly6C hi inflammatory monocytes. Science —8. Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6Chi monocyte precursors.
Mucosal Immunol 6 — Inflammation switches the differentiation program of Ly6Chi monocytes from anti-inflammatory macrophages to inflammatory dendritic cells in the colon. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39 — Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat Immunol 15 — Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation.
Immunity 40 — Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF. Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes. Osteoblast and osteocyte: games without frontiers. Arch Biochem Biophys C :3— Trends Mol Med 20 — Kikuta J, Ishii M.
Osteoclast migration, differentiation and function: novel therapeutic target for rheumatic diseases. Rheumatology Oxford 52 — Osteoclast differentiation and activation. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects.
Blood 99 — Human osteoclasts derive from CDpositive monocytes. Br J Haematol — The critical role of IL in osteoclastogenesis. PLoS One 6 :e Osteoclast differentiation factor ODF induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochem Biophys Res Commun — Commitment and differentiation of stem cells to the osteoclast lineage. Biochem Cell Biol 76 — Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages.
Origin and kinetics of monocytes and macrophages. Semin Hematol 7 — The mononuclear phagocyte system: a new classification of macrophages, monocytes, and their precursor cells. Bull World Health Organ 46 — Volkman A. The origin and fate of the monocyte. Ser Haematol 3 — The function of the monocytes. Bibl Haematol 29 — Origin and function of tissue macrophages. Immunity 41 — Hematopoiesis: an evolving paradigm for stem cell biology. Cumano A, Godin I. Ontogeny of the hematopoietic system.
Annu Rev Immunol 25 — Embryonic development of the human hematopoietic system. Int J Dev Biol 49 — Enzan H. Electron microscopic studies of macrophages in early human yolk sacs. Acta Pathol Jpn 36 — Human embryonic hemopoiesis. Kinetics of progenitors and precursors underlying the yolk sac — liver transition. J Clin Invest 78 — Differentiation, maturation, and proliferation of macrophages in the mouse yolk sac: a light-microscopic, enzyme-cytochemical, immunohistochemical, and ultrastructural study.
J Leukoc Biol 45 — Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science —5. Microglia emerge from erythromyeloid precursors via Pu. Nat Neurosci 16 — Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. Ginhoux F, Jung S. Monocytes and macrophages: development pathways and tissue homeostasis.
Nat Rev Immunol 14 — Macrophages biology in development, homeostasis and disease. A defect of CDpositive monocytes can occur without disease. Immunobiology — IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med — The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency. Randolph GJ.
Macrophages in Marseille. Czernielewski JM, Demarchez M. Further evidence for the self-reproducing capacity of Langerhans cells in human skin. J Invest Dermatol 88 — N Engl J Med —2. Langerhans cells renew in the skin throughout life under steady-state conditions. Nat Immunol 3 — A quantifiable proliferative burst of tissue macrophages restores homeostatic macrophage populations after acute inflammation.
Eur J Immunol 41 — The proliferation kinetics of pulmonary alveolar macrophages. J Leukoc Biol 35 — Local macrophages proliferation, rather than recruitment from the blood, is a signature of T H 2 inflammation. IL-4 directly signals tissue-resident macrophages to proliferate beyond homeostatic levels controlled by CSF Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol 18 — Distinct bone marrow-derived and tissue-resident macrophage lineages proliferate at key stages during inflammation.
Nat Commun 4 Hume DA. Differentiation and heterogeneity in the mononuclear phagocyte system. Mucosal Immunol 1 — Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF Blood 98 — Immunity 15 — Cancer Immunol Immunother 42 —6.
Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency, and impaired neutrophil mobilization. Blood 84 — Macrophages Download macrophages. Download Macrophages. Figure 1. Lung macrophages stained with Wright-Giemsa. Bitesize category Cells: Bite-sized Immunology. Related Articles Th17 cells. T follicular helper cells. B Cells. Dendritic Cells. Dendritic Cells Tissue-specific. Mechanisms of triglyceride accumulation in activated macrophages.
J Leukoc Biol. The p47phox mouse knock-out model of chronic granulomatous disease. Am J Pathol. Exp Eye Res. Michl J. Dissociation of the inhibitory effects of 2-deoxyglucose on phagocytosis and ATP generation. Higher phagocytic activity of thioglycollate-elicited peritoneal macrophages is related to metabolic status of the cells. J Inflamm. Biochem J. Mol Cancer Res. Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization.
Blouin CC. Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1. J Immunol. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.
HIFmediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Tyrosine phosphorylation inhibits PKM2 to promote the warburg effect and tumor growth.
Sci Signal. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. A defective pentose phosphate pathway reduces inflammatory macrophage responses during hypercholesterolemia. Cell Rep. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism.
Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. Glycolytic stimulation is not a requirement for M2 macrophage differentiation. Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation.
Reactive oxygen species ROS homeostasis and redox regulation in cellular signaling. Int J Adv Rheumatol. Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression.
Semin Cell Dev Biol. How metabolism generates signals during innate immunity and inflammation. Loss of the SdhB, but not the SdhA, subunit of complex II triggers reactive oxygen species-dependent hypoxia-inducible factor activation and tumorigenesis.
Mol Cell Biol. Palmieri F. The mitochondrial transporter family SLC25 : physiological and pathological implications. Pfligers Arch Eur J Physiol. Exp Mol Pathol. The mechanism of tricarboxylic acid cycle regulation of fatty acid. Mitochondrial carriers in inflammation induced by bacterial endotoxin and cytokines. Biol Chem. Rates of utilization and fates of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages. Acetyl coenzyme A: A central metabolite and second messenger.
ATP-citrate lyase is essential for macrophage inflammatory response. Biochem Biophys Res Commun. The mitochondrial citrate carrier: a new player in inflammation. Biochim Biophys Acta - Bioenerg. The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol. ATP-citrate lyase links cellular metabolism to histone acetylation.
Acetylation of metabolic enzymes coordinates carbon source utilization and metabolic flux. In: Reversible Protein Acetilaton. Microtubule acetylation amplifies p38 kinase signalling and anti-inflammatory IL production. Nat Commun. Epigenetic regulation of interleukin 6 by histone acetylation in macrophages and its role in paraquat-induced pulmonary fibrosis.
Front Immunol. Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Itaconic acid is a mammalian metabolite induced during macrophage activation. J Am Chem Soc. Non-targeted metabolite profiling in activated macrophage secretion. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production.
Immune responsive gene 1 IRG1 promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. IFNs modify the proteome of legionella-containing vacuoles and restrict infection via IRG1-derived itaconic acid. PLoS Pathog. Itaconate, an isocitrate lyase directed inhibitor in Pseudomonas indigofera. J Bacteriol. Berg I. Inhibition of acetate and propionate assimilation by itaconate via propionyl-CoA carboxylase in isocitrate lyase-negative purple bacterium Rhodospirillum rubrum.
Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Nrf2 signaling pathway: pivotal roles in inflammation. Biochim Biophys Acta. Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. A microRNA93—interferon regulatory factor-9—immunoresponsive Gene-1—itaconic acid pathway modulates M2-like macrophage polarization to revascularize ischemic muscle.
Isotope tracing untargeted metabolomics reveals macrophage polarization-state-specific metabolic coordination across intracellular compartments. How mitochondrial metabolism contributes to macrophage phenotype and functions. J Mol Biol. Lysine succinylation and lysine malonylation in histones. Mol Cell Proteomics. SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol. Succinate receptor GPR91 provides a direct link between high glucose levels and rennin release in murine and rabbit kidney.
Succinate is a paracrine signal for liver damage. J Hepatol. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. CrossRef Full Text. Macrophage-derived extracellular succinate licenses neural stem cells to suppress chronic neuroinflammation. Cell Stem Cell. Global metabolite profiling of synovial fluid for the specific diagnosis of rheumatoid arthritis from other inflammatory arthritis.
Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Activation of the renal renin-angiotensin system in diabetes—new concepts. Nephrol Dial Transplant. Circulating succinate is elevated in rodent models of hypertension and metabolic disease. Am J Hypertens. Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins.
Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis.
The potential of nitric oxide releasing therapies as antimicrobial agents. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host Microbe. Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Modulation of the arginase pathway in the context of microbial pathogenesis: a metabolic enzyme moonlighting as an immune modulator.
Wu G, Morris SM. Arginine metabolism: nitric oxide and beyond. Viola A, Bronte V. Metabolic mechanisms of cancer-induced inhibition of immune responses. Inducible nitric-oxide synthase generates superoxide from the reductase domain. Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism.
Andrew P. Enzymatic function of nitric oxide synthases. Cardiovasc Res. Nathan C, Ding A. Snapshot: reactive oxygen intermediates ROI. ILinduced arginase 1 suppresses alloreactive T cells in tumor-bearing mice. Nat Med. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.
Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells. Cell Immunol. IL4I1 is a novel regulator of M2 macrophage polarization that can inhibit T cell activation via L-tryptophan and arginine depletion and IL production. Inhibition of T cell proliferation by macrophage tryptophan catabolism.
Tryptophan and the immune response. Immunol Cell Biol. Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. Cancer Res. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Kynurenine 3-monooxygenase mediates inhibition of Th17 differentiation via catabolism of endogenous aryl hydrocarbon receptor ligands.
Pharmacologic or genetic targeting of glutamine synthetase skews macrophages toward an M1-like phenotype and inhibits tumor metastasis. Metabolism and TAM functions-it takes two to tango. FEBS J. Tabas I, Bornfeldt KE. Macrophage phenotype and function in different stages of atherosclerosis. Circ Res. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages.
Mitochondrial control of immunity: beyond ATP. A guide to immunometabolism for immunologists.
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