Search results for "Knockout"
showing 10 items of 806 documents
Intrinsic TNFR2 signaling in T regulatory cells provides protection in CNS autoimmunity
2018
Significance In spite of TNF involvement in the pathogenesis of multiple sclerosis (MS), systemic TNF neutralization in MS patients was not successful. One of the possible reasons is that TNF possesses both pathogenic and protective features that may be related to TNFR1 versus TNFR2 receptor engagement. This study uncovers one of such protective functions of TNF mediated by intrinsic TNFR2 signaling in Treg cells. In mice bearing humanized TNF and TNFR2 genetic loci, TNFR2 ablation restricted to Treg cells led to reduced capacity to control Th17 cell responses, exacerbated experimental autoimmune encephalomyelitis (EAE) development, and affected the maintenance of Treg cells. These findings…
NF-κB inducing kinase (NIK) is an essential post-transcriptional regulator of T-cell activation affecting F-actin dynamics and TCR signaling
2018
NF-κB inducing kinase (NIK) is the key protein of the non-canonical NF-κB pathway and is important for the development of lymph nodes and other secondary immune organs. We elucidated the specific role of NIK in T cells using T-cell specific NIK-deficient (NIKΔT) mice. Despite showing normal development of lymphoid organs, NIKΔT mice were resistant to induction of CNS autoimmunity. T cells from NIKΔT mice were deficient in late priming, failed to up-regulate T-bet and to transmigrate into the CNS. Proteomic analysis of activated NIK-/- T cells showed de-regulated expression of proteins involved in the formation of the immunological synapse: in particular, proteins involved in cytoskeleton dy…
Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors
2007
Although endocannabinoids constitute one of the first lines of defense against pain, the anatomical locus and the precise receptor mechanisms underlying cannabinergic modulation of pain are uncertain. Clinical exploitation of the system is severely hindered by the cognitive deficits, memory impairment, motor disturbances and psychotropic effects resulting from the central actions of cannabinoids. We deleted the type 1 cannabinoid receptor (CB1) specifically in nociceptive neurons localized in the peripheral nervous system of mice, preserving its expression in the CNS, and analyzed these genetically modified mice in preclinical models of inflammatory and neuropathic pain. The nociceptor-spec…
Role of Sortilin in Models of Autoimmune Neuroinflammation
2015
Abstract The proneurotrophin receptor sortilin is a protein with dual functions, being involved in intracellular protein transport, as well as cellular signal transduction. The relevance of the receptor for various neuronal disorders, such as dementia, seizures, and brain injury, is well established. In contrast, little is known about the role of sortilin in immune cells and inflammatory diseases. The aim of our study was to elucidate the distribution of sortilin in different immune cell types in mice and humans and to analyze its function in autoimmune CNS inflammation. Sortilin was expressed most profoundly in murine and human macrophages and dendritic cells and to a much lesser extent in…
OTUB1 inhibits CNS autoimmunity by preventing IFN-γ-induced hyperactivation of astrocytes.
2019
Astrocytes are critical regulators of neuroinflammation in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Growing evidence indicates that ubiquitination of signaling molecules is an important cell‐intrinsic mechanism governing astrocyte function during MS and EAE. Here, we identified an upregulation of the deubiquitinase OTU domain, ubiquitin aldehyde binding 1 (OTUB1) in astrocytes during MS and EAE. Mice with astrocyte‐specific OTUB1 ablation developed more severe EAE due to increased leukocyte accumulation, proinflammatory gene transcription, and demyelination in the spinal cord as compared to control mice. OTUB1‐deficient astrocytes were hy…
T helper cell- and CD40-dependent germline IgM prevents chronic virus-induced demyelinating disease
2012
Generation of antiviral IgM is usually considered as a marker of a short-lived initial antibody response that is replaced by hypermutated and more-efficient IgG. However, once viruses have established a particular niche for their persistence (e.g., within the CNS), the immune system has to specifically mobilize a broad range of antimicrobial effectors to contain the pathogen in the long term. Infection of the CNS with the mouse hepatitis virus (MHV) provides a unique model situation in which the extent of inflammatory CNS disease is determined by the balance between antiviral immune control, viral replication, and immune-mediated damage. We show here that whereas antibody- or B cell-defici…
Role of the cellular prion protein in oligodendrocyte precursor cell proliferation and differentiation in the developing and adult mouse CNS
2012
There are numerous studies describing the signaling mechanisms that mediate oligodendrocyte precursor cell (OPC) proliferation and differentiation, although the contribution of the cellular prion protein (PrP c) to this process remains unclear. PrP c is a glycosyl-phosphatidylinositol (GPI)-anchored glycoprotein involved in diverse cellular processes during the development and maturation of the mammalian central nervous system (CNS). Here we describe how PrP c influences oligodendrocyte proliferation in the developing and adult CNS. OPCs that lack PrP c proliferate more vigorously at the expense of a delay in differentiation, which correlates with changes in the expression of oligodendrocyt…
Mice lacking Plexin-B3 display normal CNS morphology and behaviour
2009
Semaphorins and their receptors, plexins, have emerged as important regulators of a multitude of biological processes. Plexin-B3 has been shown to be selectively expressed in postnatal oligodendrocytes. In contrast to the well-characterized Plexin-A family and the Plexin-B family members Plexin-B1 and -B2, no data are available on the functional role of Plexin-B3 in the central nervous system in vivo. Here we have elucidated the functional significance of Plexin-B3 by generating and analyzing constitutive knock-out mice. Plexin-B3-deficient mice were found to be viable and fertile. A systematic histological analysis revealed no morphological defects in the brain or spinal cord of mutant ani…
Kif3a interacts with Dynactin subunit p150 Glued to organize centriole subdistal appendages.
2013
Formation of cilia, microtubule-based structures that function in propulsion and sensation, requires Kif3a, a subunit of Kinesin II essential for intraflagellar transport (IFT). We have found that, Kif3a is also required to organize centrioles. In the absence of Kif3a, the subdistal appendages of centrioles are disorganized and lack p150(Glued) and Ninein. Consequently, microtubule anchoring, centriole cohesion and basal foot formation are abrogated by loss of Kif3a. Kif3a localizes to the mother centriole and interacts with the Dynactin subunit p150(Glued) . Depletion of p150(Glued) phenocopies the effects of loss of Kif3a, indicating that Kif3a recruitment of p150(Glued) is critical for s…
The angiopoietin-Tie2 pathway regulates Purkinje cell dendritic morphogenesis in a cell-autonomous manner.
2021
Neuro-vascular communication is essential to synchronize central nervous system development. Here, we identify angiopoietin/Tie2 as a neuro-vascular signaling axis involved in regulating dendritic morphogenesis of Purkinje cells (PCs). We show that in the developing cerebellum Tie2 expression is not restricted to blood vessels, but it is also present in PCs. Its ligands angiopoietin-1 (Ang1) and angiopoietin-2 (Ang2) are expressed in neural cells and endothelial cells (ECs), respectively. PC-specific deletion of Tie2 results in reduced dendritic arborization, which is recapitulated in neural-specific Ang1-knockout and Ang2 full-knockout mice. Mechanistically, RNA sequencing reveals that Tie…