0000000000002452
AUTHOR
Christina F. Vogelaar
Targeting CD52 does not affect murine neuron and microglia function.
The humanized anti-CD52 antibody alemtuzumab is successfully used in the treatment of multiple sclerosis (MS) and is thought to exert most of its therapeutic action by depletion and repopulation of mainly B and T lymphocytes. Although neuroprotective effects of alemtuzumab have been suggested, direct effects of anti-CD52 treatment on glial cells and neurons within the CNS itself have not been investigated so far. Here, we show CD52 expression in murine neurons, astrocytes and microglia, both in vitro and in vivo. As expected, anti CD52-treatment caused profound lymphopenia and improved disease symptoms in mice subjected to experimental autoimmune encephalomyelitis (EAE). CD52 blockade also …
Pharmacological Suppression of CNS Scarring by Deferoxamine Reduces Lesion Volume and Increases Regeneration in an In Vitro Model for Astroglial-Fibrotic Scarring and in Rat Spinal Cord Injury In Vivo.
Lesion-induced scarring is a major impediment for regeneration of injured axons in the central nervous system (CNS). The collagen-rich glial-fibrous scar contains numerous axon growth inhibitory factors forming a regeneration-barrier for axons. We demonstrated previously that the combination of the iron chelator 2,2'-bipyridine-5,5'-decarboxylic acid (BPY-DCA) and 8-Br-cyclic AMP (cAMP) inhibits scar formation and collagen deposition, leading to enhanced axon regeneration and partial functional recovery after spinal cord injury. While BPY-DCA is not a clinical drug, the clinically approved iron chelator deferoxamine mesylate (DFO) may be a suitable alternative for anti-scarring treatment (A…
The Cerebral Thrombin System Is Activated after Intracerebral Hemorrhage and Contributes to Secondary Lesion Growth and Poor Neurological Outcome in C57Bl/6 Mice
With increasing evidence for the existence of a cerebral thrombin system, coagulation factor IIa (thrombin) is suspected to influence the pathogenesis of secondary injury progression after intracerebral hemorrhage (ICH). We hypothesized that mechanisms associated with local volume expansion after ICH, rather than blood constituents, activate the cerebral thrombin system and are responsible for detrimental neurological outcome. To test this hypothesis, we examine the local thrombin expression after ICH in a C57BL/6N mouse model in the presence and absence of blood constituents. ICH was established using stereotaxic orthotopic injection of utologous blood (
Fast direct neuronal signaling via the IL-4 receptor as therapeutic target in neuroinflammation.
Ongoing axonal degeneration is thought to underlie disability in chronic neuroinflammation, such as multiple sclerosis (MS), especially during its progressive phase. Upon inflammatory attack, axons undergo pathological swelling, which can be reversible. Because we had evidence for beneficial effects of T helper 2 lymphocytes in experimental neurotrauma and discovered interleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed at unraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstrate that intrathecal IL-4 treatment during the chronic phase of several experimental autoimmune encephalomyelitis models reversed disease progression without affecting inflamma…
Extrinsic and intrinsic mechanisms of axon regeneration: the need for spinal cord injury treatment strategies to address both
Spinal cord injury (SCI) causes disturbances in motor and sensory functions leading to paralysis, the severity of which depends on the spinal level of the injury. Traumatic lesions of spinal cord axon projection tracts are untreatable in human patients, although numerous research groups worldwide are studying putative treatment strategies. Both extrinsic factors in the environment of the axons as well as intrinsic factors in the neurons themselves play important roles in the regeneration process (Chew et al., 2012). The peripheral nervous system (PNS) provides a good example where the extrinsic and intrinsic factors play optimally together to allow regeneration. Schwann cells dedifferentiat…
A predominantly glial origin of axonal ribosomes after nerve injury
Axonal mRNA transport and local protein synthesis are crucial for peripheral axon regeneration. To date, it remains unclear how ribosomes localize to axons. They may be co-transported with mRNAs or, as suggested by recent studies, transferred from Schwann cells (SC). Here, we generated transgenic "RiboTracker" mice expressing tdTomato-tagged ribosomal protein L4 in specific cell types when crossed with Cre lines. Two neuronal RiboTracker-Cre lines displayed extremely low levels of axonal L4-tdTomato-positive ribosomes. In contrast, two glial RiboTracker-Cre lines revealed tagged ribosomes in sciatic nerve (SN) axons with increasing amounts after injury. Furthermore, non-RiboTracker dorsal r…
CNS-localized myeloid cells capture living invading T cells during neuroinflammation
Using an in vivo real-time approach, the authors show that local myeloid cells remove early CNS-invading T cells via an engulfment pathway that is dependent on N-acetyl-D-glucosamine (GlcNAc) and lectin. These results reveal a novel capacity of myeloid cells to counteract neuroinflammation.
MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4
A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4-producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4-deficient animals had decreased functi…
Cortical gene expression in spinal cord injury and repair: insight into the functional complexity of the neural regeneration program
Traumatic spinal cord injury (SCI) results in the formation of a fibrous scar acting as a growth barrier for regenerating axons at the lesion site. We have previously shown (Klapka et al., 2005) that transient suppression of the inhibitory lesion scar in rat spinal cord leads to long distance axon regeneration, retrograde rescue of axotomized cortical motoneurons, and improvement of locomotor function. Here we applied a systemic approach to investigate for the first time specific and dynamic alterations in the cortical gene expression profile following both thoracic SCI and regeneration-promoting anti-scarring treatment (AST). In order to monitor cortical gene expression we carried out micr…