A Promising Small Molecule for Vanishing White Matter Disease

Investigators from Calico Life Sciences LLC and AbbVie report the effects of a novel drug targeting the genetic basis of Vanishing White Matter Disease (VWMD)

Anticonvulsant Medications in Mitochondrial Disease

Researchers from Vienna, Austria and Sao Paulo, Brazil studied the known effects of anticonvulsant drugs on mitochondria, using a literature search to include only references to epilepsy associated with mitochondrial disease, and a specific anti-convulsant drug (i.e. levetiracetam) with a specific mitochondrial function (i.e. mitochondrial membrane potential)

SDF1 in the dorsal corticospinal tract promotes CXCR4+ cell migration after spinal cord injury

<p>Abstract</p> <p>Background</p> <p>Stromal cell-derived factor-1 (SDF1) and its major signaling receptor, CXCR4, were initially described in the immune system; however, they are also expressed in the nervous system, including the spinal cord. After spinal cord injury, the blood brain barrier is compromised, opening the way for chemokine signaling between these two systems. These experiments clarified prior contradictory findings on normal expression of SDF1 and CXCR4 as well as examined the resulting spinal cord responses resulting from this signaling.</p> <p>Methods</p> <p>These experiments examined the expression and function of SDF1 and CXCR4 in the normal and injured adult mouse spinal cord primarily using CXCR4-EGFP and SDF1-EGFP transgenic reporter mice.</p> <p>Results</p> <p>In the uninjured spinal cord, SDF1 was expressed in the dorsal corticospinal tract (dCST) as well as the meninges, whereas CXCR4 was found only in ependymal cells surrounding the central canal. After spinal cord injury (SCI), the pattern of SDF1 expression did not change rostral to the lesion but it disappeared from the degenerating dCST caudally. By contrast, CXCR4 expression changed dramatically after SCI. In addition to the CXCR4+ cells in the ependymal layer, numerous CXCR4+ cells appeared in the peripheral white matter and in the dorsal white matter localized between the dorsal corticospinal tract and the gray matter rostral to the lesion site. The non-ependymal CXCR4+ cells were found to be NG2+ and CD11b+ macrophages that presumably infiltrated through the broken blood-brain barrier. One population of macrophages appeared to be migrating towards the dCST that contains SDF1 rostral to the injury but not towards the caudal dCST in which SDF1 is no longer present. A second population of the CXCR4+ macrophages was present near the SDF1-expressing meningeal cells.</p> <p>Conclusions</p> <p>These observations suggest that attraction of CXCR4+ macrophages is part of a programmed response to injury and that modulation of the SDF1 signaling system may be important for regulating the inflammatory response after SCI.</p

Diffusion Tensor Imaging of Epileptogenic Lesions in TSC

Investigators from University of California Los Angeles, studied whether epileptogenic tubers in Tuberous Sclerosis Complex (TSC) can be identified by diffusion tensor imaging (DTI)

Localized CCR2 Activation in the Bone Marrow Niche Mobilizes Monocytes by Desensitizing CXCR4

<div><p>Inflammatory (classical) monocytes residing in the bone marrow must enter the bloodstream in order to combat microbe infection. These monocytes express high levels of CCR2, a chemokine receptor whose activation is required for them to exit the bone marrow. How CCR2 is locally activated in the bone marrow and how their activation promotes monocyte egress is not understood. Here, we have used double transgenic lines that can visualize CCR2 activation <i>in vivo</i> and show that its chemokine ligand CCL2 is acutely released by stromal cells in the bone marrow, which make direct contact with CCR2-expressing monocytes. These monocytes also express CXCR4, whose activation immobilizes cells in the bone marrow, and are in contact with stromal cells expressing CXCL12, the CXCR4 ligand. During the inflammatory response, CCL2 is released and activates the CCR2 on neighboring monocytes. We demonstrate that acutely isolated bone marrow cells co-express CCR2 and CXCR4, and CCR2 activation desensitizes CXCR4. Inhibiting CXCR4 by a specific receptor antagonist in mice causes CCR2-expressing cells to exit the bone marrow in absence of inflammatory insults. Taken together, these results suggest a novel mechanism whereby the local activation of CCR2 on monocytes in the bone marrow attenuates an anchoring signalling provided by CXCR4 expressed by the same cell and mobilizes the bone marrow monocyte to the blood stream. Our results also provide a generalizable model that cross-desensitization of chemokine receptors fine-tunes cell mobility by integrating multiple chemokine signals.</p></div

CCR2-positive cells are neighbored by CXCL12-positive cells in the bone marrow.

<p>(inset) Transgenic reporter mice used in this study. (A-C) Bone marrow of CCL2::CCL2-mRFP; CXCR4::EGFP double transgenic mice. Note that CXCR4::EGFP is a transcriptional reporter, and therefore EGFP localizes to the entire cell in which CXCR4 is expressed (C). Most CCL2-mRFP cells are in close proximity to CXCR4::EGFP cells (green arrow) under normal conditions. After LPS injection, these CXCR4::EGFP cells now contain CCL2-mRFP granules (yellow arrow), indicating endocytosis of CCL2-mRFP/CCR2 (unlabeled endogenous CCR2) (B’). (D-F) Bone marrow of CXCL12::CXCL12-mRFP; CCR2::CCR2-EGFP mice. CCR2-postive cells (green arrow) are often in contact with CXCL12-positive cells (red arrow). Upon LPS injection, CCR2 is activated (white arrow: granular CCR2-EGFP signal) independently from CXCL12 signaling (because CXCL12-mRFP is not endocytosed by CCR2 positive cells). (G-I) Bone marrow of CXCL12::CXCL12-mRFP; CXCR4:EGFP mice. CXCR4 activation, which could have been visualized by CXCL12 (red arrow) endocytosis by CXCR4-positive cells (green arrow), is not increased by LPS injections. Scale bars, 10 μm.</p

Proposed model: monocyte egress by CCR2-mediated cross-desensitization of CXCR4.

<p>Monocytes in the bone marrow co-express CXCR4 and CCR2. These cells are juxtaposed to bone marrow-resident cells, which express their respective ligands, CXCL12 and CCL2. (A) Under normal conditions, monocytes are retained by CXCR4 signaling, which is activated by constitutively secreted CXCL12. CCR2 on these monocytes is not active as its ligand CCL2 is stored but not released. (B) During inflammation, stored CCL2 is rapidly released and activates CCR2, which desensitizes CXCR4 and promotes cell migration.</p

CCR2 and CXCR4 are co-expressed by bone marrow cells.

<p>(A) Acutely isolated bone marrow cells were plated on a cover slip and their responses to CCL2 (10 nM) and CXCL12 (10 nM) were measured by Fura 2-based calcium imaging. The response to ATP, which increases intracellular [Ca²⁺] by purinergic receptors, indicates that the recorded cell was alive. (B) Venn diagram showing percentage of CCL2- and/or CXCL12-responsive cells. (C) More than 80% of CCL2-responsive cells also responded to CXCL12.</p