Delayed administration of interleukin-4 coacervate alleviates the neurotoxic phenotype of astrocytes and promotes functional recovery after a contusion spinal cord injury.

. Macrophages and astrocytes play a crucial role in the aftermath of a traumatic spinal cord injury (SCI). Infiltrating macrophages adopt a pro-inflammatory phenotype while resident astrocytes adopt a neurotoxic phenotype at the injury site, both of which contribute to neuronal death and inhibit axonal regeneration.

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.

Lesion level-dependent systemic muscle wasting after spinal cord injury is mediated by glucocorticoid signaling in mice.

An incomplete mechanistic understanding of skeletal muscle wasting early after spinal cord injury (SCI) precludes targeted molecular interventions. Here, we demonstrated systemic wasting that also affected innervated nonparalyzed (supralesional) muscles and emerged within 1 week after experimental SCI in mice. Systemic muscle wasting caused muscle weakness, affected fast type 2 myofibers preferentially, and became exacerbated after high (T3) compared with low (T9) thoracic paraplegia, indicating lesion level-dependent ("neurogenic") mechanisms.

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.

Chronic demyelination and myelin repair after spinal cord injury in mice: A potential link for glutamatergic axon activity.

Our prior work examining endogenous repair after spinal cord injury (SCI) in mice revealed that large numbers of new oligodendrocytes (OLs) are generated in the injured spinal cord, with peak oligodendrogenesis between 4 and 7 weeks post-injury (wpi). We also detected new myelin formation over 2 months post-injury (mpi). Our current work significantly extends these results, including quantification of new myelin through 6 mpi and concomitant examination of indices of demyelination.

Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury.

Background And Objectives: Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane.

Methods: This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up).

Microglia states and nomenclature: A field at its crossroads.

Microglial research has advanced considerably in recent decades yet has been constrained by a rolling series of dichotomies such as "resting versus activated" and "M1 versus M2." This dualistic classification of good or bad microglia is inconsistent with the wide repertoire of microglial states and functions in development, plasticity, aging, and diseases that were elucidated in recent years. New designations continuously arising in an attempt to describe the different microglial states, notably defined using transcriptomics and proteomics, may easily lead to a misleading, although unintentional, coupling of categories and functions.

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.

Genetic deletion of the glucocorticoid receptor in Cxcr1 myeloid cells is neuroprotective and improves motor recovery after spinal cord injury.

Glucocorticoid receptors (GRs), part of the nuclear receptor superfamily of transcription factors (TFs), are ubiquitously expressed in all cell types and regulate cellular responses to glucocorticoids (e.g., cortisol in humans; corticosterone in rodents).

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.

Microglia maintain the normal structure and function of the hippocampal astrocyte network.

Microglial control of activity-dependent plasticity and synaptic remodeling in neuronal networks has been the subject of intense research in the past several years. Although microglia-neuron interactions have been extensively studied, less is known about how microglia influence astrocyte-dependent control over neuronal structure and function. Here, we explored a role for microglia in regulating the structure and function of the astrocyte syncytium in mouse hippocampus.

Wolframin is a novel regulator of tau pathology and neurodegeneration.

Selective neuronal vulnerability to protein aggregation is found in many neurodegenerative diseases including Alzheimer's disease (AD). Understanding the molecular origins of this selective vulnerability is, therefore, of fundamental importance. Tau protein aggregates have been found in Wolframin (WFS1)-expressing excitatory neurons in the entorhinal cortex, one of the earliest affected regions in AD.

Thoracic VGluT2 Spinal Interneurons Regulate Structural and Functional Plasticity of Sympathetic Networks after High-Level Spinal Cord Injury.

Traumatic spinal cord injury (SCI) above the major spinal sympathetic outflow (T6 level) disinhibits sympathetic neurons from supraspinal control, causing systems-wide "dysautonomia." We recently showed that remarkable structural remodeling and plasticity occurs within spinal sympathetic circuitry, creating abnormal sympathetic reflexes that exacerbate dysautonomia over time. As an example, thoracic VGluT2 spinal interneurons (SpINs) become structurally and functionally integrated with neurons that comprise the spinal-splenic sympathetic network and immunological dysfunction becomes progressively worse after SCI.

Central nervous system injury-induced immune suppression.

Central nervous system trauma is a common cause of morbidity and mortality. Additionally, these injuries frequently occur in younger individuals, leading to lifetime expenses for patients and caregivers and the loss of opportunity for society. Despite this prevalence and multiple attempts to design a neuroprotectant, clinical trials for a pharmacological agent for the treatment of traumatic brain injury (TBI) or spinal cord injury (SCI) have provided disappointing results.

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.

Liver inflammation at the time of spinal cord injury enhances intraspinal pathology, liver injury, metabolic syndrome and locomotor deficits.

The current high obesity rates mean that neurological injuries are increasingly sustained on a background of systemic pathology, including liver inflammation, which likely has a negative impact on outcomes. Because obesity involves complex pathology, the effect of hepatic inflammation alone on neurological recovery is unknown. Thus, here we used a gain-of-function model to test if liver inflammation worsens outcome from spinal cord injury (SCI) in rats.

Neuroimmunological therapies for treating spinal cord injury: Evidence and future perspectives.

Spinal cord injury (SCI) has a complex pathophysiology. Following the initial physical trauma to the spinal cord, which may cause vascular disruption, hemorrhage, mechanical injury to neural structures and necrosis, a series of biomolecular cascades is triggered to evoke secondary injury. Neuroinflammation plays a major role in the secondary injury after traumatic SCI.

Acute Dose-Dependent Neuroprotective Effects of Poly(pro-17β-estradiol) in a Mouse Model of Spinal Contusion Injury.

17β-Estradiol (E2) confers neuroprotection in preclinical models of spinal cord injury when administered systemically. The goal of this study was to apply E2 locally to the injured spinal cord for a sustained duration using poly(pro-E2) film biomaterials. Following contusive spinal cord injury in adult male mice, poly(pro-E2) films were implanted subdurally and neuroprotection was assessed using immunohistochemistry 7 days after injury and implantation.

The neuroanatomical-functional paradox in spinal cord injury.

Although lesion size is widely considered to be the most reliable predictor of outcome after CNS injury, lesions of comparable size can produce vastly different magnitudes of functional impairment and subsequent recovery. This neuroanatomical-functional paradox is likely to contribute to the many failed attempts to independently replicate findings from animal models of neurotrauma. In humans, the analogous clinical-radiological paradox could explain why individuals with similar injuries can respond differently to rehabilitation.