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.

Traumatic brain injury is a risk factor for subsequent neurodegenerative disease, including chronic traumatic encephalopathy, a tauopathy mostly associated with repetitive concussion and blast, but not well recognized as a consequence of severe traumatic brain injury. Here we show that a single severe brain trauma is associated with the emergence of widespread hyperphosphorylated tau pathology in a proportion of humans surviving late after injury. In parallel experimental studies, in a model of severe traumatic brain injury in wild-type mice, we found progressive and widespread tau pathology, replicating the findings in humans. Brain homogenates from these mice, when inoculated into the hippocampus and overlying cerebral cortex of naïve mice, induced widespread tau pathology, synaptic loss, and persistent memory deficits. These data provide evidence that experimental brain trauma induces a self-propagating tau pathology, which can be transmitted between mice, and call for future studies aimed at investigating the potential transmissibility of trauma associated tau pathology in humans.

BackgroundThe study of microglia and macrophage (M/M) morphology represents a key tool to understand the functional activation state and the pattern of distribution of these cells in acute brain injury. The identification of reliable quantitative morphological parameters is urgently needed to understand these cell roles in brain injury and to explore strategies aimed at therapeutically manipulating the inflammatory response.MethodsWe used three different clinically relevant murine models of focal injury, namely, controlled cortical impact brain injury (traumatic brain injury (TBI)) and transient and permanent occlusion of middle cerebral artery (tMCAo and pMCAo, respectively). Twenty-four hours after injury, M/M cells were labeled by CD11b, and ×40 photomicrographs were acquired by unbiased sampling of the lesion core using a motorized stage microscope. Images were processed with Fiji software to obtain shape descriptors.ResultsWe validated several parameters, including area, perimeter, Feret’s diameter (caliper), circularity, aspect ratio, and solidity, providing quantitative information on M/M morphology over wide tissue portions. We showed that the shape descriptors that best represent M/M ramification/elongation are area and perimeter, while circularity and solidity provide information on the ameboid shape. We also provide evidence of the involvement of different populations in local inflammatory events, with macrophages replacing microglia into the lesion core when reperfusion does not occur. Analysis of CD45high+ cell morphology, whose shape does not change, did not yield any difference, thus confirming the reliability of the approach.ConclusionsWe have defined specific morphological features that M/M acquire in response to different acute insults by applying a sensitive and readily applicable approach to cell morphological analysis in the brain tissue. Potential application of this method can be extended to all cell types able to change shape following activation, e.g., astrocytes, or to different disease states, including chronic pathologies.

These findings indicate that human umbilical cord blood mesenchymal stem cells stimulate the injured brain and evoke trophic events, microglia/macrophage phenotypical switch, and glial scar inhibitory effects that remodel the brain and lead to significant improvement of neurologic outcome.