IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

Macrophages and microglia play a key role in the maintenance of nervous system homeostasis. However, upon different challenges, they can adopt several phenotypes, which may lead to divergent effects on tissue repair. After spinal cord injury (SCI), microglia and macrophages show predominantly pro-inflammatory activation and contribute to tissue damage. However, the factors that hamper their conversion to an anti-inflammatory state after SCI, or to other protective phenotypes, are poorly understood. Here, we show that IL-4 protein levels are undetectable in the spinal cord after contusion injury, which likely favors microglia and macrophages to remain in a pro-inflammatory state. We also demonstrate that a single delayed intraspinal injection of IL-4, 48 hours after SCI, induces increased expression of M2 marker in microglia and macrophages. We also show that delayed injection of IL-4 leads to the appearance of resolution-phase macrophages, and that IL-4 enhances resolution of inflammation after SCI. Interestingly, we provide clear evidence that delayed administration of IL-4 markedly improves functional outcomes and reduces tissue damage after contusion injury. It is possible that these improvements are mediated by the presence of macrophages with M2 markers and resolution-phase macrophages. These data suggest that therapies aimed at increasing IL-4 levels could be valuable for the treatment of acute SCI, for which there are currently no effective treatments

Dual Role of Lysophosphatidic Acid Receptor 2 (LPA2) in Amyotrophic Lateral Sclerosis

Lysophosphatidic acid (LPA) is a pleiotropic extracellular lipid mediator with many physiological functions that signal through six known G protein-coupled receptors (LPA1-6). In the central nervous system (CNS), LPA mediates a wide range of effects including neural progenitor cell physiology, neuronal cell death, axonal retraction, and inflammation. Since inflammation is a hallmark of most neurological conditions, we hypothesized that LPA could be involved in the physiopathology of amyotrophic lateral sclerosis (ALS). We found that LPA2 RNA was upregulated in post-mortem spinal cord samples of ALS patients and in the sciatic nerve and skeletal muscle of SOD1G93A mouse, the most widely used ALS mouse model. To assess the contribution of LPA2 to ALS, we generated a SOD1G93A mouse that was deficient in Lpar2. This animal revealed that LPA2 signaling accelerates disease onset and neurological decline but, unexpectedly, extended the lifespan. To gain insights into the early harmful actions of LPA2 in ALS, we studied the effects of this receptor in the spinal cord, peripheral nerve, and skeletal muscle of ALS mice. We found that LPA2 gene deletion increased microglial activation but did not contribute to motoneuron death, astrogliosis, degeneration, and demyelination of motor axons. However, we observed that Lpar2 deficiency protected against muscle atrophy. Moreover, we also found the deletion of Lpar2 reduced the invasion of macrophages into the skeletal muscle of SOD1G93A mice, linking LPA2 signaling with muscle inflammation and atrophy in ALS. Overall, these results suggest for the first time that LPA2 contributes to ALS, and its genetic deletion results in protective actions at the early stages of the disease but shortens survival thereafter

CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1G93A transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1G93A mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1G93A mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease

CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves

Inflammation is a common neuropathological feature in several neurological disorders, including amyotrophic lateral sclerosis (ALS). We have studied the contribution of CSF1R signalling to inflammation in ALS, as a pathway previously reported to control the expansion and activation of microglial cells. We found that microglial cell proliferation in the spinal cord of SOD1(G93A) transgenic mice correlates with the expression of CSF1R and its ligand CSF1. Administration of GW2580, a selective CSF1R inhibitor, reduced microglial cell proliferation in SOD1(G93A) mice, indicating the importance of CSF1-CSF1R signalling in microgliosis in ALS. Moreover, GW2580 treatment slowed disease progression, attenuated motoneuron cell death and extended survival of SOD1(G93A) mice. Electrophysiological assessment revealed that GW2580 treatment protected skeletal muscle from denervation prior to its effects on microglial cells. We found that macrophages invaded the peripheral nerve of ALS mice before CSF1R-induced microgliosis occurred. Interestingly, treatment with GW2580 attenuated the influx of macrophages into the nerve, which was partly caused by the monocytopenia induced by CSF1R inhibition. Overall, our findings provide evidence that CSF1R signalling regulates inflammation in the central and peripheral nervous system in ALS, supporting therapeutic targeting of CSF1R in this disease

Desmontando mi colección. Exergos sobre la exposición

Los distintos miembros del Grupo de Investigación FIDEX (Figuras del exceso. Políticas del cuerpo) de la Universidad Miguel Hernández, explican a los alumnos de la Facultad de Bellas Artes y público en general los distintos parámetros discursivos y de producción de sus respectivas obras expuestas en la exhibición "The Collector", que tuvo lugar en la Sala de Exposiciones de la Facultad de Bellas Artes de la Universidad de Málaga desde el 3 al 31 de octubre de 2019.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1G93A ALS mice and after partial muscle denervation

Altres ajuts: Fundació La Marato-TV3(TV3201428-10), AFM-Telethon (Nrg14ALS)Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motoneurons, which is preceded by loss of neuromuscular connections in a "dying back" process. Neuregulin-1 (Nrg1) is a neurotrophic factor essential for the development and maintenance of neuromuscular junctions, and Nrg1 receptor ErbB4 loss-of-function mutations have been reported as causative for ALS. Our main goal was to investigate the role of Nrg1 type I (Nrg1-I) in SOD1G93A mice muscles. We overexpressed Nrg1-I by means of an adeno-associated viral (AAV) vector, and investigated its effect by means of neurophysiological techniques assessing neuromuscular function, as well as molecular approaches (RT-PCR, western blot, immunohistochemistry, ELISA) to determine the mechanisms underlying Nrg1-I action. AAV-Nrg1-I intramuscular administration promoted motor axon collateral sprouting by acting on terminal Schwann cells, preventing denervation of the injected muscles through Akt and ERK1/2 pathways. We further used a model of muscle partial denervation by transecting the L4 spinal nerve. AAV-Nrg1-I intramuscular injection enhanced muscle reinnervation by collateral sprouting, whereas administration of lapatinib (ErbB receptor inhibitor) completely blocked it. We demonstrated that Nrg1-I plays a crucial role in the collateral reinnervation process, opening a new window for developing novel ALS therapies for functional recovery rather than preservation

Evolutionary, ecological and biotechnological perspectives on plasmids resident in the human gut mobile metagenome

Numerous mobile genetic elements (MGE) are associated with the human gut microbiota and collectively referred to as the gut mobile metagenome. The role of this flexible gene pool in development and functioning of the gut microbial community remains largely unexplored, yet recent evidence suggests that at least some MGE comprising this fraction of the gut microbiome reflect the co-evolution of host and microbe in the gastro-intestinal tract. In conjunction, the high level of novel gene content typical of MGE coupled with their predicted high diversity, suggests that the mobile metagenome constitutes an immense and largely unexplored gene-space likely to encode many novel activities with potential biotechnological or pharmaceutical value, as well as being important to the development and functioning of the gut microbiota. Of the various types of MGE that comprise the gut mobile metagenome, plasmids are of particular importance since these elements are often capable of autonomous transfer between disparate bacterial species, and are known to encode accessory functions that increase bacterial fitness in a given environment facilitating bacterial adaptation. In this article current knowledge regarding plasmids resident in the human gut mobile metagenome is reviewed, and available strategies to access and characterize this portion of the gut microbiome are described. The relative merits of these methods and their present as well as prospective impact on our understanding of the human gut microbiota is discussed

Increased expression of colony-stimulating factor-1 in mouse spinal cord with experimental autoimmune encephalomyelitis correlates with microglial activation and neuronal loss.

Microglia contribute to pathophysiology at all stages of multiple sclerosis. Colony-stimulating factor-1 (CSF1) is crucial for microglial proliferation and activation. In this study we measured the CSF1 levels and studied its cellular expression in the mouse spinal cords with experimental autoimmune encephalomyelitis (EAE) to explore the potential contribution of CSF1 in neuronal death. ELISA data showed that CSF1 levels were significantly higher in the spinal cords with acute and chronic EAE than those of normal and adjuvant-injected mice. Immunohistochemical studies demonstrated that CSF1 was expressed in astrocytes and neurons in normal mouse spinal cord. In acute EAE, CSF1 expression was significantly increased, especially in astrocytes in peripheral white matter and large motoneurons. High density of activated microglia was observed in the gray matter where motoneurons expressed high-level CSF1 in acute EAE. Significant large motoneuron loss was seen in chronic EAE and the remaining motoneurons with high-level CSF1 were enwrapped by microglia. Viral vector mediated over-expression of CSF1 in spinal neurons induced profound proliferation and activation of microglia at the injection site and microglia enwrapped CSF1-transduced neurons and their neurites. Significant loss of large CSF1-transduced neurons was seen at 2 and 3 weeks post-viral injection. Demyelination in the CSF1-transduced areas was also significant. These results implicate that CSF1 upregulation in CNS may play an important role in the proliferation and activation of microglia in EAE, contributing to neuroinflammation and neurodegeneration. © 2018 Wiley Periodicals, Inc.Foresight Inc

Time course study of long-term biocompatibility and foreign body reaction to intraneural polyimide-based implants

The foreign body reaction (FBR) against an implanted device is characterized by the formation of a fibrotic tissue around the implant. In the case of interfaces for peripheral nerves, used to stimulate specific group of axons and to record different nerve signals, the FBR induces a matrix deposition around the implant creating a physical separation between nerve fibers and the interface that may reduce its functionality over time. In order to understand how the FBR to intraneural interfaces evolves, polyimide non-functional devices were implanted in rat peripheral nerve. Functional tests (electrophysiological, pain and locomotion) and histological evaluation demonstrated that implanted devices did not cause any alteration in nerve function, in myelinated axons or in nerve architecture. The inflammatory response due to the surgical implantation decreased after 2 weeks. In contrast, inflammation was higher and more prolonged in the device implanted nerves with a peak after 2 weeks. With regard to tissue deposition, a tissue capsule appeared soon around the devices, acquiring maximal thickness at 2 weeks and being remodeled subsequently. Immunohistochemical analysis revealed two different cell types implicated in the FBR in the nerve: macrophages as the first cells in contact with the interface and fibroblasts that appear later at the edge of the capsule. Our results describe how the FBR against a polyimide implant in the peripheral nerve occurs and which are the main cellular players. Increasing knowledge of these responses will help to improve strategies to decrease the FBR against intraneural implants and to extend their usability