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1.
Eur J Immunol ; 54(1): e2250274, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37822141

RESUMEN

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. In this review, we describe immunological and metabolic consequences of SCI across several organs. Since infection and metabolic disorders are primary reasons for reduced lifespan after SCI, it is imperative that research continues to focus on these deleterious aspects of SCI to improve life span and quality of life for individuals with SCI.


Asunto(s)
Calidad de Vida , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Inflamación , Médula Espinal/patología , Hígado/patología
2.
J Immunol ; 209(1): 157-170, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35697382

RESUMEN

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. Using mouse models of severe high-level SCI, we find that recruitment of circulating leukocytes and transcriptional control of immune signaling in the lung is impaired after SCI, creating an environment that is permissive for infection. Specifically, we saw a sustained loss of pulmonary leukocytes, a loss of alveolar macrophages at chronic time points postinjury, and a decrease in immune modulatory genes, especially cytokines, needed to eliminate pulmonary infections. Importantly, this injury-dependent impairment of pulmonary antimicrobial defense is only partially overcome by boosting the recruitment of immune cells to the lung with the drug AMD3100, a Food and Drug Administration-approved drug that mobilizes leukocytes and hematopoietic stem cells from bone marrow. Collectively, these data indicate that the immune-suppressive effects of SCI extend to the lung, a unique site of mucosal immunity. Furthermore, preventing lung infection after SCI will likely require novel strategies, beyond the use of orthodox antibiotics, to reverse or block tissue-specific cellular and molecular determinants of pulmonary immune surveillance.


Asunto(s)
Traumatismos de la Médula Espinal , Animales , Citocinas , Modelos Animales de Enfermedad , Inmunidad , Pulmón , Ratones , Médula Espinal
3.
J Neurosci ; 40(47): 9103-9120, 2020 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-33051350

RESUMEN

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. Here, we show that serial systemic injections of LPS (1 mg/kg, i.p., daily) for 4 consecutive days (LPSx4) consistently elicit a reactive spinal cord microglia response marked by dramatic morphologic changes, increased production of IL-1, and enhanced proliferation without triggering leukocyte recruitment or overt neuropathology. Following LPSx4, reactive microglia frequently contact spinal cord endothelial cells. Targeted ablation or selective expression of IL-1 and IL-1 receptor (IL-1R) in either microglia or endothelia reveal that IL-1-dependent signaling between these cells mediates microglia activation. Using a mouse model of ischemic spinal cord injury in male and female mice, we show that preoperative LPSx4 provides complete protection from ischemia-induced neuron loss and hindlimb paralysis. Neuroprotection is partly reversed by either pharmacological elimination of microglia or selective removal of IL-1R in microglia or endothelia. These data indicate that spinal cord microglia are amenable to therapeutic reprogramming via systemic manipulation and that this potential can be harnessed to protect the spinal cord from injury.SIGNIFICANCE STATEMENT Data in this report indicate that a neuroprotective spinal cord microglia response can be triggered by daily systemic injections of LPS over a period of 4 d (LPSx4). The LPSx4 regimen induces morphologic transformation and enhances proliferation of spinal cord microglia without causing neuropathology. Using advanced transgenic mouse technology, we show that IL-1-dependent microglia-endothelia cross talk is necessary for eliciting this spinal cord microglia phenotype and also for conferring optimal protection to spinal motor neurons from ischemic spinal cord injury (ISCI). Collectively, these novel data show that it is possible to consistently elicit spinal cord microglia via systemic delivery of inflammogens to achieve a therapeutically effective neuroprotective response against ISCI.


Asunto(s)
Comunicación Celular/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Interleucina-1/fisiología , Lipopolisacáridos/farmacología , Microglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Médula Espinal/efectos de los fármacos , Animales , Bromodesoxiuridina/farmacología , Células Endoteliales/metabolismo , Femenino , Interleucina-1/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/patología , Parálisis/inducido químicamente , Receptores Tipo I de Interleucina-1/efectos de los fármacos , Receptores Tipo I de Interleucina-1/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Médula Espinal/metabolismo
4.
Brain Behav Immun ; 72: 22-33, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29175543

RESUMEN

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. HMGB1 is a ubiquitously expressed DNA binding protein and also a potent inflammatory stimulus. Necrotic cells release HGMB1, but HMGB1 also is actively secreted by inflammatory macrophages. A goal of this study was to quantify spatio-temporal patterns of cellular HMGB1 expression in a controlled mouse model of experimental SCI then determine the effects of HMGB1 on post-SCI neuroinflammation and recovery of function. We documented SCI-induced changes in nuclear and cytoplasmic distribution of HMGB1 in various cell types after SCI. The data reveal a time-dependent increase in HMGB1 mRNA and protein with protein reaching maximal levels 24-72 h post-injury then declining toward baseline 14-28 days post-SCI. Although most cells expressed nuclear HMGB1, reduced nuclear labeling with increased cytoplasmic expression was found in a subset of CNS macrophages suggesting that those cells begin to secrete HMGB1 at the injury site. In vitro data indicate that extracelluar HMGB1 helps promote the development of macrophages with a neurotoxic phenotype. The ability of HMGB1 to elicit neurotoxic macrophage functions was confirmed in vivo; 72 h after injecting 500 ng of recombinant HMGB1 into intact spinal cord ventral horn, inflammatory CNS macrophages co-localized with focal areas of neuronal killing. However, attempts to confer neuroprotection after SCI by blocking HMGB1 with a neutralizing antibody were unsuccessful. Collectively, these data implicate HMGB1 as a novel regulator of post-SCI inflammation and suggest that inhibition of HMGB1 could be a novel therapeutic target after SCI. Future studies will need to identify better methods to deliver optimal concentrations of HMGB1 antagonists to the injured spinal cord.


Asunto(s)
Proteína HMGB1/metabolismo , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/metabolismo , Alarminas/metabolismo , Alarminas/fisiología , Animales , Biomarcadores/sangre , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteína HMGB1/fisiología , Inflamación/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Síndromes de Neurotoxicidad/metabolismo , Convulsiones/etiología , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Receptor Toll-Like 4/metabolismo
5.
J Neurosci ; 36(23): 6352-64, 2016 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-27277810

RESUMEN

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. Therefore, we hypothesized that TLR4 signaling may regulate oligodendrogenesis after SCI. C3H/HeJ (TLR4-deficient) and control (C3H/HeOuJ) mice received a moderate midthoracic spinal contusion. TLR4-deficient mice showed worse functional recovery and reduced OL numbers compared with controls at 24 h after injury through chronic time points. Acute OL loss was accompanied by reduced ferritin expression, which is regulated by TLR4 and needed for effective iron storage. TLR4-deficient injured spinal cords also displayed features consistent with reduced OL genesis, including reduced NG2 expression, fewer BrdU-positive OLs, altered BMP4 signaling and inhibitor of differentiation 4 (ID4) expression, and delayed myelin phagocytosis. Expression of several factors, including IGF-1, FGF2, IL-1ß, and PDGF-A, was altered in TLR4-deficient injured spinal cords compared with wild types. Together, these data show that TLR4 signaling after SCI is important for OL lineage cell sparing and replacement, as well as in regulating cytokine and growth factor expression. These results highlight new roles for TLR4 in endogenous SCI repair and emphasize that altering the function of a single immune-related receptor can dramatically change the reparative responses of multiple cellular constituents in the injured CNS milieu. SIGNIFICANCE STATEMENT: Myelinating cells of the CNS [oligodendrocytes (OLs)] are killed for several weeks after traumatic spinal cord injury (SCI), but they are replaced by resident progenitor cells. How the concurrent inflammatory signaling affects this endogenous reparative response is unclear. Here, we provide evidence that immune receptor toll-like receptor 4 (TLR4) supports OL lineage cell sparing, long-term OL and OL progenitor replacement, and chronic functional recovery. We show that TLR4 signaling is essential for acute iron storage, regulating cytokine and growth factor expression, and efficient myelin debris clearance, all of which influence OL replacement. Importantly, the current study reveals that a single immune receptor is essential for repair responses after SCI, and the potential mechanisms of this beneficial effect likely change over time after injury.


Asunto(s)
Regulación de la Expresión Génica/genética , Regeneración Nerviosa/genética , Oligodendroglía/fisiología , Traumatismos de la Médula Espinal/patología , Receptor Toll-Like 4/deficiencia , Animales , Axones/patología , Diferenciación Celular/fisiología , Proliferación Celular/genética , Células Cultivadas , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Macrófagos/fisiología , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Transgénicos , Regeneración Nerviosa/fisiología , Fagocitosis/genética , Recuperación de la Función/genética , Recuperación de la Función/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Receptor Toll-Like 4/genética
6.
Sci Transl Med ; 16(751): eadi3259, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38865485

RESUMEN

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. Here, we used a mouse model of SCI to show that microglia surrounded active glutamatergic interneurons and subsequently coordinated multi-segmental excitatory synaptogenesis and expansion of sympathetic networks that control immune, neuroendocrine, and cardiovascular functions. Depleting microglia during critical periods of circuit remodeling after SCI prevented maladaptive synaptic and structural plasticity in autonomic networks, decreased the frequency and severity of autonomic dysreflexia, and prevented SCI-induced immunosuppression. Forced turnover of microglia in microglia-depleted mice restored structural and functional indices of pathological dysautonomia, providing further evidence that microglia are key effectors of autonomic plasticity. Additional data show that microglia-dependent autonomic plasticity required expression of triggering receptor expressed on myeloid cells 2 (Trem2) and α2δ-1-dependent synaptogenesis. These data suggest that microglia are primary effectors of autonomic neuroplasticity and dysautonomia after SCI in mice. Manipulating microglia may be a strategy to limit autonomic complications after SCI or other forms of neurologic disease.


Asunto(s)
Microglía , Plasticidad Neuronal , Traumatismos de la Médula Espinal , Animales , Microglía/patología , Microglía/metabolismo , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/patología , Ratones , Receptores Inmunológicos/metabolismo , Glicoproteínas de Membrana/metabolismo , Sistema Nervioso Autónomo/fisiopatología , Ratones Endogámicos C57BL , Sinapsis/metabolismo , Interneuronas/metabolismo
7.
J Neurosci ; 32(40): 13956-70, 2012 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-23035104

RESUMEN

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. p53(-/-) spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss- and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53(-/-) mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53(-/-) mice, while, similarly, p53 expression in p53(-/-) cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.


Asunto(s)
Locomoción/fisiología , Neuronas/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Regeneración de la Medula Espinal/fisiología , Proteína p53 Supresora de Tumor/fisiología , Animales , Células Cultivadas , Cicatriz/patología , Cordotomía , Conducta Exploratoria/fisiología , Genes p53 , Calor , Cojera Animal/etiología , Cojera Animal/fisiopatología , Activación de Macrófagos , Masculino , Ratones , Ratones Noqueados , Microglía/patología , Plasticidad Neuronal/fisiología , Tractos Piramidales/patología , Recuperación de la Función , Degeneración Retrógrada , Umbral Sensorial , Neuronas Serotoninérgicas/fisiología , Traumatismos de la Médula Espinal/genética , Regeneración de la Medula Espinal/genética , Proteína p53 Supresora de Tumor/deficiencia
8.
bioRxiv ; 2023 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-38187534

RESUMEN

Spinal cord injury (SCI) is a devastating condition characterized by impaired motor and sensory function, as well as internal organ pathology and dysfunction. This internal organ dysfunction, particularly gastrointestinal (GI) complications, and neurogenic bowel, can reduce the quality of life of individuals with an SCI and potentially hinder their recovery. The gut microbiome impacts various central nervous system functions and has been linked to a number of health and disease states. An imbalance of the gut microbiome, i.e., gut dysbiosis, contributes to neurological disease and may influence recovery and repair processes after SCI. Here we examine the impact of high cervical SCI on the gut microbiome and find that transient gut dysbiosis with persistent gut pathology develops after SCI. Importantly, probiotic treatment improves gut health and respiratory motor function measured through whole-body plethysmography. Concurrent with these improvements was a systemic decrease in the cytokine tumor necrosis factor-alpha and an increase in neurite sprouting and regenerative potential of neurons. Collectively, these data reveal the gut microbiome as an important therapeutic target to improve visceral organ health and respiratory motor recovery after SCI. Research Highlights: Cervical spinal cord injury (SCI) causes transient gut dysbiosis and persistent gastrointestinal (GI) pathology.Treatment with probiotics after SCI leads to a healthier GI tract and improved respiratory motor recovery.Probiotic treatment decreases systemic tumor necrosis factor-alpha and increases the potential for sprouting and regeneration of neurons after SCI.The gut microbiome is a valid target to improve motor function and secondary visceral health after SCI.

9.
J Neurosci ; 31(27): 9910-22, 2011 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-21734283

RESUMEN

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. Deficient CX3CR1 signaling in intraspinal microglia and monocyte-derived macrophages (MDMs) attenuates their ability to synthesize and release inflammatory cytokines and oxidative metabolites. Also, impaired CX3CR1 signaling abrogates the recruitment or maturation of MDMs with presumed neurotoxic effects after SCI. Indeed, in wild-type mice, Ly6C(lo)/iNOS(+)/MHCII(+)/CD11c(-) MDMs dominate the lesion site, whereas CCR2(+)/Ly6C(hi)/MHCII(-)/CD11c(+) monocytes predominate in the injured spinal cord of CX3CR1-deficient mice. Replacement of wild-type MDMs with those unable to signal via CX3CR1 resulted in anatomical and functional improvements after SCI. Thus, blockade of CX3CR1 signaling represents a selective anti-inflammatory therapy that is able to promote neuroprotection, in part by reducing inflammatory signaling in microglia and MDMs and recruitment of a novel monocyte subset.


Asunto(s)
Antígenos Ly/metabolismo , Macrófagos/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Receptores de Quimiocina/deficiencia , Recuperación de la Función/genética , Transducción de Señal/fisiología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Análisis de Varianza , Animales , Antígenos CD11/metabolismo , Receptor 1 de Quimiocinas CX3C , Células Cultivadas , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Regulación de la Expresión Génica/genética , Proteínas Fluorescentes Verdes/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Actividad Motora/genética , Actividad Motora/fisiología , Proteína Básica de Mielina/metabolismo , Óxido Nítrico/metabolismo , Transducción de Señal/genética , Traumatismos de la Médula Espinal/genética
10.
Cell Tissue Res ; 349(1): 201-13, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22592625

RESUMEN

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. By targeting both the regenerative potential of the axon and the cytotoxic phenotype of microglia/macrophages, we may be able to improve CNS repair after SCI. In this review, we discuss molecules shown to impact CNS repair by affecting both immune cells and neurons. Specifically, we provide examples of pattern recognition receptors, integrins, cytokines/chemokines, nuclear receptors and galectins that could improve CNS repair. In many cases, signaling by these molecules is complex and may have contradictory effects on recovery depending on the cell types involved or the model studied. Despite this caveat, deciphering convergent signaling pathways on immune cells (which affect axon growth indirectly) and neurons (direct effects on axon growth) could improve repair and recovery after SCI. Future studies must continue to consider how regenerative therapies targeting neurons impact other cells in the pathological CNS. By identifying molecules that simultaneously improve axon regenerative capacity and drive the protective, growth-promoting phenotype of immune cells, we may discover SCI therapies that act synergistically to improve CNS repair and functional recovery.


Asunto(s)
Axones/inmunología , Axones/fisiología , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/fisiología , Regeneración Nerviosa/inmunología , Transducción de Señal/inmunología , Animales , Humanos , Receptores de Reconocimiento de Patrones/metabolismo
11.
Curr Opin Pharmacol ; 64: 102230, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35489214

RESUMEN

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. Although it is widely appreciated that mature leukocyte dysfunction is a canonical feature of SCI-IDS, new data indicate that SCI impairs the development and mobilization of immune cell precursors in bone marrow. Thus, this review will also explore how the post-injury acquisition of a "bone marrow failure syndrome" may be the earliest manifestation of SCI-IDS.


Asunto(s)
Enfermedades del Sistema Inmune , Traumatismos de la Médula Espinal , Médula Ósea , Humanos , Transducción de Señal
12.
Nat Commun ; 13(1): 4096, 2022 07 14.
Artículo en Inglés | MEDLINE | ID: mdl-35835751

RESUMEN

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. We show that microglia are vital for SCI recovery and coordinate injury responses in CNS-resident glia and infiltrating leukocytes. Depleting microglia exacerbates tissue damage and worsens functional recovery. Conversely, restoring select microglia-dependent signaling axes, identified through sequencing data, in microglia depleted mice prevents secondary damage and promotes recovery. Additional bioinformatics analyses reveal that optimal repair after SCI might be achieved by co-opting key ligand-receptor interactions between microglia, astrocytes and MDMs.


Asunto(s)
Traumatismos de la Médula Espinal , Regeneración de la Medula Espinal , Animales , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Microglía/patología , Médula Espinal/patología
13.
mSystems ; 6(3)2021 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-33975974

RESUMEN

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. Here, SCI-induced gut dysbiosis was assessed by applying genome- and gene-resolved metagenomic analysis of murine stool samples collected 21 days after an experimental SCI at the 4th thoracic spine (T4) or 10th thoracic spine (T10) spinal level. These distinct injuries partially (T10) or completely (T4) abolish sympathetic tone in the gut. Among bacteria, 105 medium- to high-quality metagenome-assembled genomes (MAGs) were recovered, with most (n = 96) representing new bacterial species. Read mapping revealed that after SCI, the relative abundance of beneficial commensals (Lactobacillus johnsonii and CAG-1031 spp.) decreased, while potentially pathogenic bacteria (Weissella cibaria, Lactococcus lactis _A, Bacteroides thetaiotaomicron) increased. Functionally, microbial genes encoding proteins for tryptophan, vitamin B6, and folate biosynthesis, essential pathways for central nervous system function, were reduced after SCI. Among viruses, 1,028 mostly novel viral populations were recovered, expanding known murine gut viral species sequence space ∼3-fold compared to that of public databases. Phages of beneficial commensal hosts (CAG-1031, Lactobacillus, and Turicibacter) decreased, while phages of pathogenic hosts (Weissella, Lactococcus, and class Clostridia) increased after SCI. Although the microbiomes and viromes were changed in all SCI mice, some of these changes varied as a function of spinal injury level, implicating loss of sympathetic tone as a mechanism underlying gut dysbiosis.IMPORTANCE To our knowledge, this is the first article to apply metagenomics to characterize changes in gut microbial population dynamics caused by a clinically relevant model of central nervous system (CNS) trauma. It also utilizes the most current approaches in genome-resolved metagenomics and viromics to maximize the biological inferences that can be made from these data. Overall, this article highlights the importance of autonomic nervous system regulation of a distal organ (gut) and its microbiome inhabitants after traumatic spinal cord injury (SCI). By providing information on taxonomy, function, and viruses, metagenomic data may better predict how SCI-induced gut dysbiosis influences systemic and neurological outcomes after SCI.

14.
J Neurosci ; 29(43): 13435-44, 2009 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-19864556

RESUMEN

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., "classically activated" proinflammatory (M1) or "alternatively activated" anti-inflammatory (M2) cells. Here, we show that an M1 macrophage response is rapidly induced and then maintained at sites of traumatic spinal cord injury and that this response overwhelms a comparatively smaller and transient M2 macrophage response. The high M1/M2 macrophage ratio has significant implications for CNS repair. Indeed, we present novel data showing that only M1 macrophages are neurotoxic and M2 macrophages promote a regenerative growth response in adult sensory axons, even in the context of inhibitory substrates that dominate sites of CNS injury (e.g., proteoglycans and myelin). Together, these data suggest that polarizing the differentiation of resident microglia and infiltrating blood monocytes toward an M2 or "alternatively" activated macrophage phenotype could promote CNS repair while limiting secondary inflammatory-mediated injury.


Asunto(s)
Macrófagos/fisiología , Regeneración Nerviosa/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Médula Espinal/fisiopatología , Animales , Axones/fisiología , Supervivencia Celular , Células Cultivadas , Corteza Cerebral/fisiopatología , Proteoglicanos Tipo Condroitín Sulfato/metabolismo , Ganglios Espinales/fisiopatología , Ratones , Ratones Endogámicos C57BL , Microglía/fisiología , Monocitos/fisiología , Vaina de Mielina/metabolismo , Células Receptoras Sensoriales/fisiología , Factores de Tiempo , Degeneración Walleriana/fisiopatología
15.
Acta Neuropathol ; 119(1): 123-33, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-19946692

RESUMEN

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. Whereas spinal cord sections prepared from non-injured laminectomy control animals contained low basal levels of progranulin immunoreactivity in gray matter, sections from injured animals contained intense immunoreactivity throughout the injury epicenter that peaked 7-14 days post injury. Progranulin immunoreactivity colocalized with myeloid cell markers CD11b and CD68, indicating that expression increased primarily in activated microglia and macrophages. Immunoblot analysis confirmed that progranulin protein levels rose after injury. On the basis of quantitative polymerase chain reaction analysis, increased protein levels resulted from a tenfold rise in progranulin transcripts. These data demonstrate that progranulin is dramatically induced in myeloid cells after experimental spinal cord injury and is positioned appropriately both spatially and temporally to influence recovery after injury.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Traumatismos de la Médula Espinal/metabolismo , Médula Espinal/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígeno CD11b/metabolismo , Femenino , Granulinas , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Fibras Nerviosas Amielínicas/metabolismo , Neuroinmunomodulación , Progranulinas , Vértebras Torácicas , Factores de Tiempo , Regulación hacia Arriba
16.
Curr Top Microbiol Immunol ; 336: 121-36, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19688331

RESUMEN

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. However, recently it was shown that TLRs are expressed on a range of neuronal and non-neuronal cells (e.g., glia, stem/progenitor cells and leukocytes), and that nonpathogenic molecules released from sites of tissue injury, i.e., danger-associated molecular patterns (DAMPs), can activate cells via TLRs. This review will discuss how DAMPs acting at various TLRs may influence injury and repair processes of relevance to SCI, i.e., neurotoxicity, demyelination, growth cone collapse and stem/progenitor cell turnover.


Asunto(s)
Traumatismos de la Médula Espinal/inmunología , Receptores Toll-Like/inmunología , Animales , Humanos , Degeneración Nerviosa/inmunología , Regeneración Nerviosa/inmunología
17.
Exp Neurol ; 323: 113085, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31654639

RESUMEN

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. The current review considers how SCI changes the physiological interplay between the spinal cord, the gut and the immune system. A suspected culprit in causing many of the pathological manifestations of impaired spinal cord-gut-immune axis homeostasis is the gut microbiota. After SCI, the composition of the gut microbiota changes, creating a chronic state of gut "dysbiosis". To date, much of what we know about gut dysbiosis was learned from 16S-based taxonomic profiling studies that reveal changes in the composition and abundance of various bacteria. However, this approach has limitations and creates taxonomic "blindspots". Notably, only bacteria can be analyzed. Thus, in this review we also discuss how the application of emerging sequencing technologies can improve our understanding of how the broader ecosystem in the gut is affected by SCI. Specifically, metagenomics will provide researchers with a more comprehensive look at post-injury changes in the gut virome (and mycome). Metagenomics also allows changes in microbe population dynamics to be linked to specific microbial functions that can affect the development and progression of metabolic disease, immune dysfunction and affective disorders after SCI. As these new tools become more readily available and used across the research community, the development of an "ecogenomic" toolbox will facilitate an Eco-Systems Biology approach to study the complex interplay along the spinal cord-gut-immune axis after SCI.


Asunto(s)
Enfermedades del Sistema Nervioso Autónomo , Fenómenos Fisiológicos del Sistema Digestivo , Microbioma Gastrointestinal , Fenómenos del Sistema Inmunológico , Traumatismos de la Médula Espinal , Animales , Enfermedades del Sistema Nervioso Autónomo/etiología , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Humanos , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/fisiopatología
18.
PLoS One ; 15(1): e0226128, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31940312

RESUMEN

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 objective of the current study is to establish a model of anxiety following a cervical contusion spinal cord injury in rats and to determine whether the microbiota play a role in the observed behavioural changes. We found that spinal cord injury caused dysbiosis and increased symptoms of anxiety-like behaviour. Treatment with a fecal transplant prevented both spinal cord injury-induced dysbiosis as well as the development of anxiety-like behaviour. These results indicate that an incomplete unilateral cervical spinal cord injury can cause affective disorders and intestinal dysbiosis, and that both can be prevented by treatment with fecal transplant therapy.


Asunto(s)
Ansiedad/complicaciones , Ansiedad/prevención & control , Conducta Animal , Disbiosis/complicaciones , Disbiosis/prevención & control , Trasplante de Microbiota Fecal , Traumatismos de la Médula Espinal/complicaciones , Animales , Disbiosis/microbiología , Microbioma Gastrointestinal , Aprendizaje por Laberinto , Ratas , Recuperación de la Función , Traumatismos de la Médula Espinal/microbiología , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/psicología
19.
Brain Behav Immun ; 23(6): 851-60, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19361551

RESUMEN

There is growing recognition that psychological stress influences pain. Hormones that comprise the physiological response to stress (e.g., corticosterone; CORT) may interact with effectors of neuropathic pain. To test this hypothesis, mice received a spared nerve injury (SNI) after exposure to 60 min restraint stress. In stressed mice, allodynia was consistently increased. The mechanism(s) underlying the exacerbated pain response involves CORT acting via glucocorticoid receptors (GRs); RU486, a GR antagonist, prevented the stress-induced increase in allodynia whereas exogenous administration of CORT to non-stressed mice reproduced the allodynic response caused by stress. Since nerve injury-induced microglial activation has been implicated in the onset and propagation of neuropathic pain, we evaluated cellular and molecular indices of microglial activation in the context of stress. Activation of dorsal horn microglia was accelerated by stress; however, this effect was transient and was not associated with the onset or maintenance of a pro-inflammatory phenotype. Stress-enhanced allodynia was associated with increased dorsal horn extracellular signal-regulated kinase phosphorylation (pERK). ERK activation could indicate a stress-mediated increase in glutamatergic signaling, therefore mice were treated prior to SNI and stress with memantine, an N-methyl-D-aspartate receptor (NMDAR) antagonist. Memantine prevented stress-induced enhancement of allodynia after SNI. These data suggest that the hormonal responses elicited by stress exacerbate neuropathic pain through enhanced central sensitization. Moreover, drugs that inhibit glucocorticoids (GCs) and/or NMDAR signaling could ameliorate pain syndromes caused by stress.


Asunto(s)
Dolor/etiología , Dolor/psicología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Receptores de Glucocorticoides/fisiología , Receptores de N-Metil-D-Aspartato/fisiología , Estrés Psicológico/complicaciones , Estrés Psicológico/psicología , Animales , Corticosterona/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Ratones , Ratones Endogámicos C57BL , Mifepristona/farmacología , Dolor/patología , Dimensión del Dolor/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/patología , Fosforilación , Células del Asta Posterior/efectos de los fármacos , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inhibidores , Restricción Física , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
20.
Neurotherapeutics ; 15(1): 60-67, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29101668

RESUMEN

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.e., the gut microbiota) as disease-modifying factors that are capable of affecting systemic physiology and pathophysiology. Recent data from rodents indicate that SCI causes gut dysbiosis, which exacerbates intraspinal inflammation and lesion pathology leading to impaired recovery of motor function. Postinjury delivery of probiotics containing various types of "good" bacteria can partially overcome the pathophysiologal effects of gut dysbiosis; immune function, locomotor recovery, and spinal cord integrity are partially restored by a sustained regimen of oral probiotics. More research is needed to determine whether gut dysbiosis varies across a range of clinically relevant variables, including sex, injury level, and injury severity, and whether changes in the gut microbiota can predict the onset or severity of common postinjury comorbidities, including infection, anemia, metabolic syndrome, and, perhaps, secondary neurological deterioration. Those microbial populations that dominate the gut could become "druggable" targets that could be manipulated via dietary interventions. For example, personalized nutraceuticals (e.g., pre- or probiotics) could be developed to treat the above comorbidities and improve health and quality of life after SCI.


Asunto(s)
Sistema Nervioso Autónomo/microbiología , Disbiosis , Microbioma Gastrointestinal , Traumatismos de la Médula Espinal/microbiología , Animales , Sistema Nervioso Autónomo/fisiopatología , Humanos , Inflamación/etiología , Inflamación/microbiología , Traumatismos de la Médula Espinal/complicaciones
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