The ischemic environment drives microglia and macrophage function.
TL;DR: The selective responses of microglia and macrophages to hypoxia after stroke are discussed and relevant markers are reviewed with the aim of defining the different subpopulations of myeloid cells that are recruited to the injured site.
Abstract: Cells of myeloid origin, such as microglia and macrophages, act at the crossroads of several inflammatory mechanisms during pathophysiology. Besides pro-inflammatory activity (M1 polarization), myeloid cells acquire protective functions (M2) and participate in the neuroprotective innate mechanisms after brain injury. Experimental research is making considerable efforts to understand the rules that regulate the balance between toxic and protective brain innate immunity. Environmental changes affect microglia/macrophage functions. Hypoxia can affect myeloid cell distribution, activity, and phenotype. With their intrinsic differences, microglia and macrophages respond differently to hypoxia, the former depending on ATP to activate and the latter switching to anaerobic metabolism and adapting to hypoxia. Myeloid cell functions include homeostasis control, damage-sensing activity, chemotaxis, and phagocytosis, all distinctive features of these cells. Specific markers and morphologies enable to recognize each functional state. To ensure homeostasis and activate when needed, microglia/macrophage physiology is finely tuned. Microglia are controlled by several neuron-derived components, including contact-dependent inhibitory signals and soluble molecules. Changes in this control can cause chronic activation or priming with specific functional consequences. Strategies, such as stem cell treatment, may enhance microglia protective polarization. This review presents data from the literature that has greatly advanced our understanding of myeloid cell action in brain injury. We discuss the selective responses of microglia and macrophages to hypoxia after stroke and review relevant markers with the aim of defining the different subpopulations of myeloid cells that are recruited to the injured site. We also cover the functional consequences of chronically active microglia and review pivotal works on microglia regulation that offer new therapeutic possibilities for acute brain injury.
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TL;DR: The diversity of microglia phenotypes and their responses in health, aging, and disease are described and treatment options that modulate microglial phenotypes are discussed.
Abstract: As the immune-competent cells of the brain, microglia play an increasingly important role in maintaining normal brain function. They invade the brain early in development, transform into a highly ramified phenotype, and constantly screen their environment. Microglia are activated by any type of pathologic event or change in brain homeostasis. This activation process is highly diverse and depends on the context and type of the stressor or pathology. Microglia can strongly influence the pathologic outcome or response to a stressor due to the release of a plethora of substances, including cytokines, chemokines, and growth factors. They are the professional phagocytes of the brain and help orchestrate the immunological response by interacting with infiltrating immune cells. We describe here the diversity of microglia phenotypes and their responses in health, aging, and disease. We also review the current literature about the impact of lifestyle on microglia responses and discuss treatment options that modulate microglial phenotypes.
900 citations
TL;DR: Key studies on modulators of microglial activation and polarization after ICH are summarized, including M1-like and M2-like microglia phenotype markers, transcription factors and key signalling pathways, and the evidence that therapeutic approaches aimed at modulating microglian function might mitigate ICH injury and improve brain repair is presented.
Abstract: Intracerebral haemorrhage (ICH) is the most lethal subtype of stroke but currently lacks effective treatment Microglia are among the first non-neuronal cells on the scene during the innate immune response to ICH Microglia respond to acute brain injury by becoming activated and developing classic M1-like (proinflammatory) or alternative M2-like (anti-inflammatory) phenotypes This polarization implies as yet unrecognized actions of microglia in ICH pathology and recovery, perhaps involving microglial production of proinflammatory or anti-inflammatory cytokines and chemokines Furthermore, alternatively activated M2-like microglia might promote phagocytosis of red blood cells and tissue debris, a major contribution to haematoma clearance Interactions between microglia and other cells modulate microglial activation and function, and are also important in ICH pathology This Review summarizes key studies on modulators of microglial activation and polarization after ICH, including M1-like and M2-like microglial phenotype markers, transcription factors and key signalling pathways Microglial phagocytosis, haematoma resolution, and the potential crosstalk between microglia and T lymphocytes, neurons, astrocytes, and oligodendrocytes in the ICH brain are described Finally, the clinical and translational implications of microglial polarization in ICH are presented, including the evidence that therapeutic approaches aimed at modulating microglial function might mitigate ICH injury and improve brain repair
490 citations
TL;DR: This review summarizes recent progress concerning the mechanisms involved in brain damage, repair and regeneration related to microglia/macrophage activation and phenotype transition after stroke and argues that future translational studies should be targeting multiple key regulating molecules to improve brain repair.
445 citations
Cites background from "The ischemic environment drives mic..."
...Some molecules that are essential for the regulation of the development of microglia/macrophages in stroke have already been described (Boche et al., 2013; Fumagalli et al., 2015; Weinstein et al., 2010; Zhou et al., 2014)....
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TL;DR: New potential therapeutics need to interfere with these diabetic complications even before changes in the retina are diagnosed, to prevent neuronal apoptosis and blindness in patients.
Abstract: Diabetic retinopathy is a common complication of diabetes mellitus, which appears in one third of all diabetic patients and is a prominent cause of vision loss. First discovered as a microvascular disease, intensive research in the field identified inflammation and neurodegeneration to be part of diabetic retinopathy. Microglia, the resident monocytes of the retina, are activated due to a complex interplay between the different cell types of the retina and diverse pathological pathways. The trigger for developing diabetic retinopathy is diabetes-induced hyperglycemia, accompanied by leukostasis and vascular leakages. Transcriptional changes in activated microglia, mediated via the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and extracellular signal–regulated kinase (ERK) signaling pathways, results in release of various pro-inflammatory mediators, including cytokines, chemokines, caspases and glutamate. Activated microglia additionally increased proliferation and migration. Among other consequences, these changes in microglia severely affected retinal neurons, causing increased apoptosis and subsequent thinning of the nerve fiber layer, resulting in visual loss. New potential therapeutics need to interfere with these diabetic complications even before changes in the retina are diagnosed, to prevent neuronal apoptosis and blindness in patients.
212 citations
Cites background from "The ischemic environment drives mic..."
...Microglia are altered by hyperglycemia, ischemia, hypoxia, dyslipidemia and endoplasmic reticulum stress, but the exact mode of microglia activation in DR is still unknown [125,126,128]....
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TL;DR: The frontiers of current knowledge of innate and adaptive immune responses in the brain and how these responses together shape the course of ischemic stroke are explored.
Abstract: Over the past several decades, there have been substantial advances in our knowledge of the pathophysiology of stroke. Understanding the benefits of timely reperfusion has led to the development of thrombolytic therapy as the cornerstone of current management of ischemic stroke, but there remains much to be learned about mechanisms of neuronal ischemic and reperfusion injury and associated inflammation. For ischemic stroke, novel therapeutic targets have continued to remain elusive. When considering modern molecular biological techniques, advanced translational stroke models, and clinical studies, a consistent pattern emerges, implicating perturbation of the immune equilibrium by stroke in both central nervous system injury and repair responses. Stroke triggers activation of the neuroimmune axis, comprised of multiple cellular constituents of the immune system resident within the parenchyma of the brain, leptomeninges, and vascular beds, as well as through secretion of biological response modifiers and recruitment of immune effector cells. This neuroimmune activation can directly impact the initiation, propagation, and resolution phases of ischemic brain injury. To leverage a potential opportunity to modulate local and systemic immune responses to favorably affect the stroke disease curve, it is necessary to expand our mechanistic understanding of the neuroimmune axis in ischemic stroke. This review explores the frontiers of current knowledge of innate and adaptive immune responses in the brain and how these responses together shape the course of ischemic stroke.
178 citations
Cites background from "The ischemic environment drives mic..."
...Common characteristics include the expression of phenotypic markers, phagocytic behavior, and extraordinary plasticity necessary to respond to a diverse array of inflammatory inputs.(93) However, recent studies have revealed distinct transcriptional mechanisms that control these unique functional responses....
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...In the inflamed CNS, microglia and macrophages share some common, but also some distinct features.(93) Common characteristics include the expression of phenotypic markers, phagocytic behavior, and extraordinary plasticity necessary to respond to a diverse array of inflammatory inputs....
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References
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TL;DR: The evidence in favour of alternative macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 is assessed, and its limits and relevance to a range of immune and inflammatory conditions are defined.
Abstract: The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
5,930 citations
TL;DR: Recent evidence suggests that differential modulation of the chemokine system integrates polarized macrophages in pathways of resistance to, or promotion of, microbial pathogens and tumors, or immunoregulation, tissue repair and remodeling.
5,568 citations
TL;DR: These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.
4,728 citations
TL;DR: The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for Macrophage-centered diagnostic and therapeutic strategies.
Abstract: Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
4,721 citations
"The ischemic environment drives mic..." refers background in this paper
...In neurodegenerative disorders, myeloid cells often present mixed phenotypes indicating their plastic nature and their ability to acquire multiple phenotypes in response to environmental signals and time-dependent changes in the inflammatory milieu (83)....
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...TLR4 has a pivotal role in the promotion of the M1 polarization (83)....
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...These antigenic fingerprints for polarization are well mirrored in some pathological conditions in vivo, including parasite infections, allergy, and cancer (83)....
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...TLRs are expressed by myeloid cells in response to activation and are involved in the switch toward M1 polarization (83) either by inducing NF-κB, which in turn induces pro-inflammatory cytokines (TNFα, IL-12, SOCS3) and HIF-1α to promote iNOS synthesis, or by inducing IRF-3, one of the main transcriptional regulators initiating M1...
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...In particular, stimulation through toll-like receptor (TLR) ligands and INF-γ induces classical M1 activation, while IL-4/IL-13 stimulation favors the alternative M2 activation (83)....
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TL;DR: The four stages of orderly inflammation mediated by macrophages are discussed: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis.
Abstract: Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing Finally, we briefly discuss the characterization of macrophage heterogeneity in humans
4,182 citations
"The ischemic environment drives mic..." refers background in this paper
...MCP-1/CCL2 is a potent chemoattractant for monocytes and may have a role in tissue repair and regeneration (222)....
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