Microglia promote maladaptive plasticity in autonomic circuitry after spinal cord injury in mice.

Robust structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry after severe high-level spinal cord injury (SCI). As a result, normally innocuous visceral or somatic stimuli elicit uncontrolled activation of spinal sympathetic reflexes that contribute to systemic disease and organ-specific pathology. How hyperexcitable sympathetic circuitry forms is unknown, but local cues from neighboring glia likely help mold these maladaptive neuronal networks.

System failure: Systemic inflammation following spinal cord injury.

Spinal cord injury (SCI) affects hundreds of thousands of people in the United States, and while some effects of the injury are broadly recognized (deficits to locomotion, fine motor control, and quality of life), the systemic consequences of SCI are less well-known. The spinal cord regulates systemic immunological and visceral functions; this control is often disrupted by the injury, resulting in viscera including the gut, spleen, liver, bone marrow, and kidneys experiencing local tissue inflammation and physiological dysfunction. The extent of pathology depends on the injury level, severity, and time post-injury.

Microglia coordinate cellular interactions during spinal cord repair in mice.

Traumatic spinal cord injury (SCI) triggers a neuro-inflammatory response dominated by tissue-resident microglia and monocyte derived macrophages (MDMs). Since activated microglia and MDMs are morphologically identical and express similar phenotypic markers in vivo, identifying injury responses specifically coordinated by microglia has historically been challenging. Here, we pharmacologically depleted microglia and use anatomical, histopathological, tract tracing, bulk and single cell RNA sequencing to reveal the cellular and molecular responses to SCI controlled by microglia.

Spinal Cord Injury Impairs Lung Immunity in Mice.

Pulmonary infection is a leading cause of morbidity and mortality after spinal cord injury (SCI). Although SCI causes atrophy and dysfunction in primary and secondary lymphoid tissues with a corresponding decrease in the number and function of circulating leukocytes, it is unknown whether this SCI-dependent systemic immune suppression also affects the unique tissue-specific antimicrobial defense mechanisms that protect the lung. In this study, we tested the hypothesis that SCI directly impairs pulmonary immunity and subsequently increases the risk for developing pneumonia.

Immune dysfunction after spinal cord injury - A review of autonomic and neuroendocrine mechanisms.

Infections impair neurological outcome and increase mortality after spinal cord injury (SCI). Emerging data show that pathogens more easily infect individuals with SCI because SCI disrupts neural and humoral control of immune cells, culminating with the development of "SCI-induced immune deficiency syndrome" (SCI-IDS). Here, we review data that implicate autonomic dysfunction and impaired neuroendocrine signaling as key determinants of SCI-IDS.

Spinal Cord Injury Changes the Structure and Functional Potential of Gut Bacterial and Viral Communities.

Emerging data indicate that gut dysbiosis contributes to many human diseases, including several comorbidities that develop after traumatic spinal cord injury (SCI). To date, all analyses of SCI-induced gut dysbiosis have used 16S rRNA amplicon sequencing. This technique has several limitations, including being susceptible to taxonomic "blind spots," primer bias, and an inability to profile microbiota functions or identify viruses.

Serial Systemic Injections of Endotoxin (LPS) Elicit Neuroprotective Spinal Cord Microglia through IL-1-Dependent Cross Talk with Endothelial Cells.

Microglia are dynamic immunosurveillance cells in the CNS. Whether microglia are protective or pathologic is context dependent; the outcome varies as a function of time relative to the stimulus, activation state of neighboring cells in the microenvironment or within progression of a particular disease. Although brain microglia can be "primed" using bacterial lipopolysaccharide (LPS)/endotoxin, it is unknown whether LPS delivered systemically can also induce neuroprotective microglia in the spinal cord.

Fecal transplant prevents gut dysbiosis and anxiety-like behaviour after spinal cord injury in rats.

Secondary manifestations of spinal cord injury beyond motor and sensory dysfunction can negatively affect a person's quality of life. Spinal cord injury is associated with an increased incidence of depression and anxiety; however, the mechanisms of this relationship are currently not well understood. Human and animal studies suggest that changes in the composition of the intestinal microbiota (dysbiosis) are associated with mood disorders.

The spinal cord-gut-immune axis as a master regulator of health and neurological function after spinal cord injury.

Most spinal cord injury (SCI) research programs focus only on the injured spinal cord with the goal of restoring locomotor function by overcoming mechanisms of cell death or axon regeneration failure. Given the importance of the spinal cord as a locomotor control center and the public perception that paralysis is the defining feature of SCI, this "spinal-centric" focus is logical. Unfortunately, such a focus likely will not yield new discoveries that reverse other devastating consequences of SCI including cardiovascular and metabolic disease, bladder/bowel dysfunction and infection.

High mobility group box-1 (HMGB1) is increased in injured mouse spinal cord and can elicit neurotoxic inflammation.

Inflammation is a ubiquitous but poorly understood consequence of spinal cord injury (SCI). The mechanisms controlling this response are unclear but culminate in the sequential activation of resident and recruited immune cells. Collectively, these cells can exert divergent effects on cell survival and tissue repair.

Gut Microbiota Are Disease-Modifying Factors After Traumatic Spinal Cord Injury.

Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS), impairing its ability to coordinate organ function throughout the body. Emerging data indicate that the systemic pathology that manifests from ANS dysfunction exacerbates intraspinal pathology and neurological impairment. Precisely how this happens is unknown, although new data, in both humans and in rodent models, implicate changes in the composition of bacteria in the gut (i.

Gut dysbiosis impairs recovery after spinal cord injury.

The trillions of microbes that exist in the gastrointestinal tract have emerged as pivotal regulators of mammalian development and physiology. Disruption of this gut microbiome, a process known as dysbiosis, causes or exacerbates various diseases, but whether gut dysbiosis affects recovery of neurological function or lesion pathology after traumatic spinal cord injury (SCI) is unknown. Data in this study show that SCI increases intestinal permeability and bacterial translocation from the gut.

TLR4 Deficiency Impairs Oligodendrocyte Formation in the Injured Spinal Cord.

Unlabelled: Acute oligodendrocyte (OL) death after traumatic spinal cord injury (SCI) is followed by robust neuron-glial antigen 2 (NG2)-positive OL progenitor proliferation and differentiation into new OLs. Inflammatory mediators are prevalent during both phases and can influence the fate of NG2 cells and OLs. Specifically, toll-like receptor (TLR) 4 signaling induces OL genesis in the naive spinal cord, and lack of TLR4 signaling impairs white matter sparing and functional recovery after SCI.

Traumatic spinal cord injury in mice with human immune systems.

Mouse models have provided key insight into the cellular and molecular control of human immune system function. However, recent data indicate that extrapolating the functional capabilities of the murine immune system into humans can be misleading. Since immune cells significantly affect neuron survival and axon growth and also are required to defend the body against infection, it is important to determine the pathophysiological significance of spinal cord injury (SCI)-induced changes in human immune system function.

Pattern recognition receptors and central nervous system repair.

Pattern recognition receptors (PRRs) are part of the innate immune response and were originally discovered for their role in recognizing pathogens by ligating specific pathogen associated molecular patterns (PAMPs) expressed by microbes. Now the role of PRRs in sterile inflammation is also appreciated, responding to endogenous stimuli referred to as "damage associated molecular patterns" (DAMPs) instead of PAMPs. The main families of PRRs include Toll-like receptors (TLRs), Nod-like receptors (NLRs), RIG-like receptors (RLRs), AIM2-like receptors (ALRs), and C-type lectin receptors.

p53 Regulates the neuronal intrinsic and extrinsic responses affecting the recovery of motor function following spinal cord injury.

Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53(-/-) versus wild-type mice.

Achieving CNS axon regeneration by manipulating convergent neuro-immune signaling.

After central nervous system (CNS) trauma, axons have a low capacity for regeneration. Regeneration failure is associated with a muted regenerative response of the neuron itself, combined with a growth-inhibitory and cytotoxic post-injury environment. After spinal cord injury (SCI), resident and infiltrating immune cells (especially microglia/macrophages) contribute significantly to the growth-refractory milieu near the lesion.

Macrophage migration inhibitory factor (MIF) is essential for inflammatory and neuropathic pain and enhances pain in response to stress.

Stress and glucocorticoids exacerbate pain via undefined mechanisms. Macrophage migration inhibitory factor (MIF) is a constitutively expressed protein that is secreted to maintain immune function when glucocorticoids are elevated by trauma or stress. Here we show that MIF is essential for the development of neuropathic and inflammatory pain, and for stress-induced enhancement of neuropathic pain.

System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo.

It is widely believed that microglia and monocyte-derived macrophages (collectively referred to as central nervous system (CNS) macrophages) cause excitotoxicity in the diseased or injured CNS. This view has evolved mostly from in vitro studies showing that neurotoxic concentrations of glutamate are released from CNS macrophages stimulated with lipopolysaccharide (LPS), a potent inflammogen. We hypothesized that excitotoxic killing by CNS macrophages is more rigorously controlled in vivo, requiring both the activation of the glutamate/cystine antiporter (system x(c)(-)) and an increase in extracellular cystine, the substrate that drives glutamate release.

Deficient CX3CR1 signaling promotes recovery after mouse spinal cord injury by limiting the recruitment and activation of Ly6Clo/iNOS+ macrophages.

Macrophages exert divergent effects in the injured CNS, causing either neurotoxicity or regeneration. The mechanisms regulating these divergent functions are not understood but can be attributed to the recruitment of distinct macrophage subsets and the activation of specific intracellular signaling pathways. Here, we show that impaired signaling via the chemokine receptor CX3CR1 promotes recovery after traumatic spinal cord injury (SCI) in mice.

Progranulin expression is upregulated after spinal contusion in mice.

Progranulin (proepithelin) is a pleiotropic growth-factor associated with inflammation and wound repair in peripheral tissues. It also has been implicated in the response to acute traumatic brain injury as well as to chronic neurodegenerative diseases. To determine whether changes in progranulin expression also accompany acute spinal cord injury, C57BL/6 mice were subjected to mid-thoracic (T9 level) contusion spinal cord injury and analyzed by immunohistochemical and biochemical methods.

Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord.

Macrophages dominate sites of CNS injury in which they promote both injury and repair. These divergent effects may be caused by distinct macrophage subsets, i.e.

Toll-like receptors in spinal cord injury.

Following traumatic spinal cord injury (SCI), activated glia and inflammatory leukocytes contribute to both neurodegeneration and repair. The mechanisms that control these divergent functions are poorly understood. Toll-like receptors (TLRs) are a highly conserved family of receptors involved in pathogen recognition and host defense.

Stress exacerbates neuropathic pain via glucocorticoid and NMDA receptor activation.

There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g.