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.
Highlights
CLASSICAL VIEW OF NEUROINFLAMMATION In the late 19th century, Paul Ehrlich observed that a water-soluble viable dye injected into the peripheral circulation stained all organs except the central nervous system (CNS), providing the first indication that the CNS was anatomically separated from the rest of the body
Recent evidence has helped define a new role for brain immune cells, highlighting their involvement in several stages of development, homeostasis, aging, or response to injury
Microglia and macrophages are the main players in neuroinflammation, and in view of their plastic nature, they may develop either toxic or protective functions
Summary
Stefano Fumagalli 1,2, Carlo Perego, Francesca Pischiutta, Elisa R. Microglia are well equipped to sense any change in tissue homeostasis thanks to the expression of different surface receptors with damage-sensing functions These receptors, generally referred to as pattern recognition receptors (PRR), bind ligands of different types: high mobility group box 1 (HMGB1), Hsp, hyaluronic acid and fibronectin produced by extracellular matrix degradation, apoptotic or injured cells, nucleic acids, immune complexes, mannose residues, and proteolytic enzymes [119]. Inhibition of ADP sensing by ticagrelor induces protection from ischemia at 48 h and is associated with reduced microglia/macrophage recruitment to the lesion site and with decreased expression of pro-inflammatory mediators, such as iNOS, IL-1β, and MCP-1 [137] This suggests that microglia have an early toxic effect that can be counteracted by inhibiting their activation and homing to the lesion. Possible consequences of the dysfunctional behavior of aged microglia include dysregulated response to injuries, changes in neuroprotective functions and increased toxic responses [200]
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