John R Bethea

• University of Miami

Spinal cord injury, SCI, is a devastating condition with 250,000 to 500,000 new cases globally each year. Respiratory infections, e.g., pneumonia and influenza are the leading cause of death after SCI.Unfortunately, there is a poor understanding of how altered neuro-immune communication impacts an individuals outcome to infection. In humans and rod...

Multiple sclerosis (MS), a demyelinating autoimmune disease of the central nervous system (CNS), predominately affects females compared to males. Tumor necrosis factor (TNF), a pro-inflammatory cytokine, signaling through TNF receptor 1 contributes to inflammatory disease pathogenesis. In contrast, TNF receptor 2 signaling is neuroprotective. Curre...

Activation of the endoplasmic reticulum (ER) stress sensor inositol‐requiring enzyme‐1α (IRE1α) contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the contrary, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activat...

Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP) [1–4]. To test the hypothesis that supraspinal circuitry is critical to pain chronification, we studied the intersect between sup...

Upregulation of soluble tumor necrosis factor (sTNF) cytokine signaling through TNF receptor 1 (TNFR1) and subsequent neuronal hyperexcitability are observed in both animal models and human chronic neuropathic pain (CNP) (Clark et al., 2013; Empl et al., 2001; Ji et al., 2018; Lindenlaub and Sommer, 2003). To test the hypothesis that supraspinal ci...

Loss of function in transport protein particles (TRAPP) links a new set of emerging genetic disorders called “TRAPPopathies”. One such disorder is NIBP syndrome, characterized by microcephaly and intellectual disability, and caused by mutations of NIBP/TRAPPC9, a crucial and unique member of TRAPPII. To investigate the neural cellular/molecular mec...

Activation of the ER stress sensor IRE1a contributes to neuronal development and is known to induce neuronal remodeling in vitro and in vivo. On the other hand, excessive IRE1 activity is often detrimental and may contribute to neurodegeneration. To determine the consequences of increased activation of IRE1a, we used a mouse model expressing a C148...

Postural control is critical for locomotion, allowing for gait changes, obstacle avoidance and navigation of rough terrain. A major problem after spinal cord injury (SCI) is regaining the control of balance to prevent falls and further injury. While the circuits for locomotor pattern generation reside in the spinal cord, postural control consists o...

Multiple Sclerosis (MS) is a debilitating autoimmune disease often accompanied by severe chronic pain. The most common type of pain in MS, called neuropathic pain, arises from disease processes affecting the peripheral and central nervous systems. It is incredibly difficult to study these processes in patients, so animal models such as experimental...

Background: The rat mid-thoracic contusion model has been used to study at-level tactile allodynia, a common type of pain that develops after spinal cord injury (SCI). An important advantage of this model is that not all animals develop hypersensitivity. Therefore, it can be used to examine mechanisms that are strictly related to the development o...

The rat mid-thoracic contusion model has been used to study at-level tactile allodynia after spinal cord injury (SCI), one of the more common types of allodynia. An important advantage of this model is that not all animals develop allodynia and, therefore, it could be used to more clearly examine mechanisms that are strictly related to pain develop...

CNS inflammation is a major driver of MS pathology. Differential immune responses, including the adaptive and the innate immune system, are observed at various stages of MS and drive disease development and progression. Next to these immune-mediated mechanisms, other mediators contribute to MS pathology. These include immune-independent cell death...

Spinal cord injury (SCI) disrupts critical, physiological systems, including the cardiovascular and immune system. Plasticity of spinal circuits below the injury results in abnormal, heightened sympathetic responses, such as extreme, sudden hypertension that hallmarks life-threatening autonomic dysreflexia. Moreover, such sympathetic hyperreflexia...

Significance Tumor necrosis factor (TNF) is a cytokine that induces signaling via two receptors, TNFR1 and TNFR2. TNF signaling via TNFR1 contributes to development and maintenance of neuropathic pain. Here, we show that TNFR2 is essential for recovery from neuropathic pain across sexes. Treatment of male and female neuropathic mice with a TNFR2 ag...

Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that promotes immune modulation and tissue regeneration and is recognized as a potential therapeutic target for multiple sclerosis (MS). However, TNFR2 also contributes to T effector cell function and macrophage-TNFR2 recently was shown to promote disease development in the experi...

Aim The activation of the TNFR2 receptor is beneficial in several pathologies of the central nervous system, and this study examines whether it can ameliorate the recovery process following spinal cord injury. Methods EHD2‐sc‐mTNFR2, an agonist specific for TNFR2, was used to treat neurons exposed to high levels of glutamate in vitro. In vivo, it...

Antiviral immunity is severely compromised following trauma to the central nervous system. In mice with chronic spinal cord injury (SCI), primary infection with influenza virus leads to high mortality rates due to impaired expansion of virus-specific CD8 T cells. One strategy to increase resistance to viral infections is to generate memory immune c...

Tumor necrosis factor (TNF) is a proinflammatory cytokine, which is involved in physiological and pathological processes and has been found to be crucial for pain development. In the current study, we were interested in the effects of blocking Tumor necrosis factor receptor 1 (TNFR1) signaling on neuropathic pain after peripheral nerve injury with...

Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is kno...

Quantitative PCR CT Values for catabolic genes in soleus muscle. Shown are CT values for target genes FOXO1, MAFbx, MURF-1, and PSMD11 normalized to Actin (2-ΔΔCt). (XLSX)

Behavioral and motor function scores. Shown are BMS composite scores for hindlimb locomotor function, rotarod time for motor coordination and balance, and hindlimb grip strength. Values include baseline/pretraining, 1-day, 2- and 4-weeks post-SCI for BMS, and baseline/pretraining, 2- and 4-weeks post-SCI for both rotarod time trial and grip strengt...

Chemiluminescence detection of target proteins in soleus muscle tissue. Shown are normalized relative intensities corresponding to chemiluminescence protein detection from immunoblots targeting the phosphorylated forms of PI3K, AKT, mTOR, and S6K. Groups include sham vs. SCI (1-, 2-, and 4-weeks), and SCI at the same timepoints with UA treatment. (...

Body mass curves and soleus muscle mass. A complete list of body mass at baseline and daily for 30 days post-SCI. Groups include sham, SCI, SCI with CO, and SCI with UA. Soleus muscle tissue was harvested at time of necropsy at 1-, 2- and 4-weeks post-SCI and mass was recorded. Groups include sham vs. SCI (1-, 2-, and 4-weeks), and SCI at the same...

Background: Spinal cord injury (SCI) disrupts essential neuroimmune communication, leading to severe immune depression. Previous studies confirmed immune dysfunction in mice with chronic SCI and following high thoracic level injury where sympathetic innervation of the spleen is disrupted. Here, we induced a mid-thoracic injury where integrity of t...

Cardiovascular disease and susceptibility to infection are leading causes of morbidity and mortality for individuals with spinal cord injury (SCI). A major contributor to these is autonomic dysreflexia (AD), an amplified reaction of the autonomic nervous system (hallmarked by severe hypertension) in response to sensory stimuli below the injury. Mal...

Traumatic injury of the central nervous system (CNS) including brain and spinal cord remains a leading cause of morbidity and disability in the world. Delineating the mechanisms underlying the secondary and persistent injury versus the primary and transient injury has been drawing extensive attention for study during the past few decades. The steri...

Background Lymphotoxin (LT) is a lymphokine mainly expressed in lymphocytes. LTα binds one or two membrane-associated LTβ to form LTα2β1 or LTα1β2 heterotrimers. The predominant LTα1β2 binds to LTβ receptor (LTβR) primarily expressed in epithelial and stromal cells. Most studies on LTβR signaling have focused on the organization, development, and m...

Nuclear factor-kappa B (NF-κB) is a key modulator of inflammation and secondary injury responses in neurodegenerative disease, including spinal cord injury (SCI). Inhibition of astroglial NF-κB reduces inflammation, enhances oligodendrogenesis and improves functional recovery after SCI, however the contribution of neuronal NF-κB to secondary inflam...

Trauma to the spinal cord disrupts essential communication between the central nervous system and the immune system. This is highly important as patients with spinal cord injury (SCI) are at greater risk for infections that increase morbidity and mortality. Previous studies have confirmed immune depression in mouse models of chronic SCI. In mice, i...

Background Individuals suffering from spinal cord injury (SCI) are at higher risk for respiratory-related viral infections such as influenza. In a previous study (Zha et al., J Neuroinflammation 11:65, 2014), we demonstrated that chronic spinal cord injury caused impairment in CD8+T cell function with increased expression of the immunosuppressive p...

Unlabelled: Tumor necrosis factor (TNF) is associated with the pathophysiology of various neurological disorders, including multiple sclerosis. It exists as a transmembrane form tmTNF, signaling via TNF receptor 2 (TNFR2) and TNFR1, and a soluble form, solTNF, signaling via TNFR1. Multiple sclerosis is associated with the detrimental effects of so...

Peripheral myelination is a dynamic process orchestrated by axons and Schwann cells. Although the signaling mechanisms governing myelination are not fully understood, NF-κB activation in Schwann cells has been implicated as a key regulator in vitro. Using a mouse model, we show that nuclear factor κB activation in Schwann cells is not required for...

Spinal cord injury results in irreversible paralysis, axonal injury, widespread oligodendrocyte death, and white matter damage. Although the mechanisms underlying these phenomena are poorly understood, previous studies from our laboratory indicate that inhibiting activation of the nuclear factor-κB transcription factor in astrocytes reduces white m...

A mutation in the IL7Rα locus has been identified as a risk factor for multiple sclerosis (MS), a neurodegenerative autoimmune disease characterized by inflammation, demyelination, and axonal damage. IL7Rα has well documented roles in lymphocyte development and homeostasis, but its involvement in disease is largely understudied. In this study, we u...

Background Optic neuritis is an acute, demyelinating neuropathy of the optic nerve often representing the first appreciable symptom of multiple sclerosis. Wallerian degeneration of irreversibly damaged optic nerve axons leads to death of retinal ganglion cells, which is the cause of permanent visual impairment. Although the specific mechanisms resp...

Naïve and sham-operated young and aged analysis of hypothalamic adipokine mRNA, leptin signaling intermediates, ER stress and UPR activation. Quantification of mRNA expression levels show that FIAF is significantly increased in sham-operated young (SY) compared to naïve young (NY) control and in sham-operated aged (SO) compared to naïve aged (NO) c...

Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation, demyelination, and axonal damage. Recently, a mutation in the interleukin-7 receptor alpha (IL7Rα) locus has been identified as a risk factor for MS. IL7Rα has well-documented roles in lymphocyte development, function, and homeostasis, but its involvement in disea...

Schwann cells (SCs) are crucial for peripheral nerve development and regeneration; however, the intrinsic regulatory mechanisms governing postinjury responses are poorly understood. Activation and deacetylation of nuclear factor-κB (NF- κB) in SCs have been implicated as prerequisites for peripheral nerve myelination. Using GFAP-IκBα-dn mice in whi...

Inflammatory mediators, many of which activate the signaling of nuclear factor kappa B (NFκB), have received increasing attention in the field of neurogenesis. NFκB signaling regulates neurite outgrowth and neural plasticity as well as the proliferation/apoptosis and terminal differentiation of neural stem cells (NSCs). Early neurogenesis from NSCs...

Tumour necrosis factor is linked to the pathophysiology of various neurodegenerative disorders including multiple sclerosis. Tumour necrosis factor exists in two biologically active forms, soluble and transmembrane. Here we show that selective inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis....

Multiple sclerosis (MS) is a neurodegenerative disease characterized by extensive inflammation, demyelination, and axonal damage. The interleukin-7 receptor alpha (IL7Rα) chain is an essential subunit for the signaling receptors of both interleukin-7 (IL7) and thymic stromal lymphopoietin (TSLP), which are involved in lymphocyte development, functi...

The interleukin-1 receptor antagonist (IL-1Ra) is the principal determinant of IL-1β bioactivity within the IL-1 gene cluster, regulating IL-1α and IL-1β release. This study was designed to determine whether polymorphisms of the IL-1Ra gene (IL1RN) produce clinically measurable differences in serum IL-1Ra concentrations and opioid consumption in th...

The IκB kinase complex induces nuclear factor kappa B activation and has recently been recognized as a key player of autoimmunity in the central nervous system. Notably, IκB kinase/nuclear factor kappa B signalling regulates peripheral myelin formation by Schwann cells, however, its role in myelin formation in the central nervous system during heal...

Astrocyte swelling and brain edema are major complications of the acute form of hepatic encephalopathy (acute liver failure, ALF). While elevated brain ammonia level is a well-known etiological factor in ALF, the mechanism by which ammonia brings about astrocyte swelling is not well understood. We recently found that astrocyte cultures exposed to a...

There is growing evidence that astrocytes play critical roles in neuron-glial interactions at the synapse. Astrocytes are believed to regulate presynaptic and postsynaptic structures and functions, in part, by the release of gliotransmitters such as glutamate, ATP, and d-serine; however, little is known of how neurons and astrocytes communicate to...

The subventricular zone (SVZ) of the mammalian forebrain is a major source of multipotent stem cells during development, and contributes to neurogenesis throughout the lifespan of the organism. Several studies described molecules regulating adult neurogenesis, however, few of them have examined neurogenesis in the early postnatal period. Adult neur...

Ephrins and Eph receptor(s) have recently been implicated in regulating neurogenesis in the adult subventricular zone (SVZ) and rostral migratory stream. Here, we examined the role of ephrinB3-EphB3 signaling in mediating the SVZ response to traumatic brain injury (TBI). Analysis of EphB3 expression showed colocalization with glial fibrillary acidi...

The transcription factor nuclear factor kappa B (NF-kappaB) is a key regulator of inflammatory processes in reactive glial cells. We utilized a transgenic mouse model (GFAP-IkappaBalpha-dn) where the classical NF-kappaB pathway is inactivated by overexpression of a dominant negative (dn) form of the inhibitor of kappa B (IkappaBalpha) in glial fibr...

Reactive astrocytes have been implicated in neuronal loss following ischemic stroke. However, the molecular mechanisms associated with this process are yet to be fully elucidated. In this work, we tested the hypothesis that astroglial NF-kappaB, a key regulator of inflammatory responses, is a contributor to neuronal death following ischemic injury....

We previously showed that Nuclear Factor kappaB (NF-kappaB) inactivation in astrocytes leads to improved functional recovery following spinal cord injury (SCI). This correlated with reduced expression of pro-inflammatory mediators and chondroitin sulfate proteoglycans, and increased white matter preservation. Hence we hypothesized that inactivation...

In the CNS, the transcription factor NF-kappaB is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-kappaB-dependent genes is activated, leading to both protective and detrimental effects. In this study, we show that transgenic inactivation of astroglial NF-kappaB (glial fibrillary aci...

In the CNS the transcription factor NF-κB is a key regulator of inflammation and secondary injury processes. Following trauma or disease, the expression of NF-κB-dependent genes is activated, leading to both protective and detrimental effects. Here we show that transgenic inactivation of astroglial NF-κB (GFAP-IκBα-dn mice) resulted in reduced dise...

Eph receptors have been implicated in regulating a diverse array of cellular functions in the developing nervous system. Recently, Eph receptors have been shown to promote cell death in adult germinal zones; however, their mechanisms of action remain ill-defined. In this study, we demonstrate that EphA4 is a new member of the dependence receptors f...

Oestrogen receptors (ERs) are important for sexual differentiation of the brain. Previous studies in rats have reported that the locus coeruleus (LC), a catecholaminergic nucleus in the brain stem, is sexually dimorphic such that females have more neurones than males. We hypothesised that ERs may be important for sexual differentiation of this nucl...

Astrocytes play a pivotal role in regulating synaptic plasticity and synapse formation. The nuclear factor-kappa B (NF-κB) family of transcription factors has recently been demonstrated to be an important modulator of synaptic plasticity and learning/memory. In this study, we investigated the role of astroglial NF-κB in synaptic plasticity and lear...

In this work, we studied transgenic glial fibrillary acidic protein-IkappaBalpha-dn mice that selectively inactivate the classical nuclear factor kappaB pathway by overexpressing the inhibitory protein of kappaBalpha in astrocytes, under the control of glial fibrillary acidic protein promoter. We sought to determine if glial nuclear factor kappaB i...

The driving forces for the regulation of cell morphology are the Rho family GTPases that coordinate the assembly of the actin cytoskeleton. This dynamic feature is a result of tight coupling between the cytoskeleton and signal transduction and is facilitated by actin-binding proteins (ABPs). Mutations in the actin bundling and PDZ domain-containing...

Following traumatic injury to the central nervous system (CNS), cytokine levels rapidly increase at the site of lesion. Cytokines are produced at high concentrations by resident cells of the brain and spinal cord parenchyma (astrocytes, neurons, microglial cells) and by immune cells (macrophages, leukocytes), infiltrating the injured tissue through...

The transcription factor NF-kappaB plays an important role in both physiological and pathological events in the central nervous system. Nevertheless, the mechanisms of NF-kappaB-mediated regulation of gene expression, and the signaling molecules participating in the NF-kappaB pathway in the central nervous system are, to date, poorly understood. To...

In the central nervous system (CNS), the transcription factor nuclear factor (NF)-kappaB is a key regulator of inflammation and secondary injury processes. After trauma or disease, the expression of NF-kappaB-dependent genes is highly activated, leading to both protective and detrimental effects on CNS recovery. We demonstrate that selective inacti...

NF-kappaB-inducing kinase (NIK) has been implicated as an essential component of NF-kappaB activation. However, the regulatory mechanism of NIK signaling remains elusive. We have identified a novel NIK interacting protein, TNAP (for TRAFs and NIK-associated protein). In mammalian cells, TNAP physically interacts with NIK, TRAF2, and TRAF3 but not I...

Axonal regeneration in the adult CNS is limited by the presence of several inhibitory proteins associated with myelin. Nogo-A, a myelin-associated inhibitor, is responsible for axonal outgrowth inhibition in vivo and in vitro. Here we study the onset and maturation of Nogo-A and Nogo receptor in the entorhino-hippocampal formation of developing and...

High-affinity excitatory amino acid transporters (EAATs) are essential to terminate glutamatergic neurotransmission and to prevent excitotoxicity. To date, five distinct EAATs have been cloned from animal and human tissues: GLAST (EAAT1), GLT-1 (EAAT2), EAAC1 (EAAT3), EAAT4, and EAAT5. EAAT1 and EAAT2 are commonly known as glial glutamate transport...

Both acute and chronic inflammatory processes have been shown to influence outcome in experimental models of spinal cord injury. Although early inflammatory responses may participate in secondary injury processes, more delayed inflammatory events may be reparative. Therapeutic strategies that target these events are currently based on experimental...

The effects of two antiinflammatory and neuroprotective agents, methylprednisolone (MP) and interleukin-10 (IL-10), singly and in combination on tissue damage, axonal preservation and functional recovery were studied in the contused adult Fischer rat thoracic spinal cord 12 weeks after injury. MP (30 mg/kg at 5 min, and 2 and 4 h after injury) was...

Nogo is a potent inhibitor of regeneration following spinal cord injury. To develop a better understanding of the mechanisms responsible for regenerative failure we used a yeast two-hybrid approach to try and identify proteins that interact with Nogo. We identified a novel mitochondrial protein designated Nogo-interacting mitochondrial protein (NIM...

RGS proteins regulate G protein-mediated signalling pathways through direct interaction with the Galpha subunits and facilitation of GTP hydrolysis. An RGS subfamily consisting of RGS 6, 7, 9, and 11 also interacts with the G protein beta subunit Gbeta5 via a characteristic Ggamma-like domain. Thus far, these complexes were found only in neurons, w...

A number of studies have provided evidence that cell death from moderate traumatic spinal cord injury (SCI) is regulated, in part, by apoptosis that involves the caspase family of cysteine proteases. However, little or no information is available about anti-apoptotic mechanisms mediated by the inhibitors of apoptosis (IAP) family of proteins that i...

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathophysiological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Responses to QUIS-induced injury include an inflammatory component, as well as the development of spontaneous and evoked pain behaviors. We hypothesized...

Ischemic neuronal cell death induced by transient ischemic attacks, cardiopulmonary arrest followed by resuscitation and acute stroke are leading causes of death and disability in industrialized countries. Early (< 3 h) treatment with tissue plasminogin activator (t-PA) was approved in 1996 for the treatment of acute stroke [1]. Nevertheless, the t...

Dynorphin A is an endogenous opioid peptide, which has previously been shown to produce a long-lasting allodynia and hyperalgesia in mice, behavioral states consistent with signs of clinically observed neuropathic pain. This dynorphin-induced allodynia was used as a pharmacological, central model of neuropathic pain. In this study, we examined the...

In these studies, we examined the neuroprotective effects of the potent antiinflammatory cytokine interleukin-10 (IL-10) following spinal cord injury (SCI). Neuroprotection was assessed by using behavioral and morphological end points. We hypothesized that injury-induced inflammation contributes to the resulting neuropathology and subsequent loss o...

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Inflammatory responses appear to be a major component of the secondary neuronal injury initiated by SCI and play a role in the pathogenesis of QUIS-induced in...

Experimental studies have demonstrated that postischemic therapeutic interventions may delay rather than provide long-lasting neuroprotection. The purpose of this study was to determine whether mild hypothermia (33-34 degrees C) combined with the anti-inflammatory cytokine interleukin-10 (IL-10) would protect the CA1 hippocampus 2 months after isch...

Inflammatory responses are a major component of secondary injury and play a central role in mediating the pathogenesis of acute and chronic spinal cord injury (SCI). The nuclear factor-kappaB (NF-kappaB) family of transcription factors is required for the transcriptional activation of a variety of genes regulating inflammatory, proliferative, and c...

LPS induces the expression of the gene encoding the type II TNF-alpha receptor in mononuclear phagocytes. To elucidate the nuclear signaling mechanisms involved in this response, a 772-bp fragment of the TNFRII gene promoter was analyzed by deletion and site-specific mutagenesis following transient transfection in the macrophage-like cell line RAW2...

In the human astroglioma cell line CH235-MG, interleukin-1 beta (IL-1 beta) induces transcriptional activation of the tumor necrosis factor-alpha (TNF-alpha) gene, resulting in expression of TNF-alpha mRNA and biologically active TNF-alpha protein. This study was undertaken to elucidate intracellular signaling pathways involved in IL-1 beta inducti...

Cells that produce tumor necrosis factor-alpha (TNF-alpha) require the presence of signaling molecules since this cytokine is not normally expressed in a constitutive manner. It has been demonstrated that glial cells can produce TNF-alpha; however, the specific inducing molecules and their mechanism(s) of action have not been clearly defined. In th...

Human malignant gliomas possess some of the same immune-related functions as astrocytes do. For instance, they are capable of secreting various immunoregulatory molecules and expressing HLA-DR antigens on their surface. The human malignant glioma cell line, D54-MG, was used to investigate the proliferative effects of tumor necrosis factor-alpha (TN...

Astrocytes can function as antigen-presenting cells (APC) upon expression of class II antigens, which are induced by interferon-gamma (IFN-gamma). Tumor necrosis factor-alpha (TNF-alpha) can act synergistically with IFN-gamma with respect to class II expression on a variety of cells. As brain cells themselves can secrete TNF-like factors upon stimu...

Cerebral ischemia leading to infarction was produced in rats by intravascular thrombosis induced by a photochemical reaction between systemically injected rose bengal and green light (560 nm) transmitted through the intact skull for a 2-min period. At 2 or 15 min following photochemical sensitization, animals were perfusion-fixed for scanning (SEM)...