Leishmania parasites have evolved sophisticated mechanisms to subvert macrophage immune responses by altering the host cell signal transduction machinery, including inhibition of JAK/STAT signalling and other transcription factors such as AP-1, CREB and NF-κB. AP-1 regulates pro-inflammatory cytokines, chemokines and nitric oxide production. Herein we show that upon Leishmania infection, AP-1 activity within host cells is abolished and correlates with lower expression of 5 of the 7 AP-1 subunits. Of interest, c-Jun, the central component of AP-1, is cleaved by Leishmania. Furthermore, the cleavage of c-Jun is dependent on the expression and activity of the major Leishmania surface protease GP63. Immunoprecipitation of c-Jun from nuclear extracts showed that GP63 interacts, and cleaves c-Jun at the perinuclear area shortly after infection. Phagocytosis inhibition by cytochalasin D did not block c-Jun down-regulation, suggesting that internalization of the parasite might not be necessary to deliver GP63 molecules inside the host cell. This observation was corroborated by the maintenance of c-Jun cleavage upon incubation with L. mexicana culture supernatant, suggesting that secreted, soluble GP63 could use a phagocytosis-independent mechanism to enter the host cell. In support of this, disruption of macrophage lipid raft microdomains by Methyl β-Cyclodextrin (MβCD) partially inhibits the degradation of full length c-Jun. Together our results indicate a novel role of the surface protease GP63 in the Leishmania-mediated subversion of host AP-1 activity.
The preferential accumulation of vascular smooth muscle cells (vSMCs) on arteries versus veins during early development is a well-described phenomenon, but the molecular pathways underlying this polarization are not well understood. In zebrafish, the cxcr4a receptor (mammalian CXCR4) and its ligand cxcl12b (mammalian CXCL12) are both preferentially expressed on arteries at time points consistent with the arrival and differentiation of the first vSMCs during vascular development. We show that autocrine cxcl12b/cxcr4 activity leads to increased production of the vSMC chemoattractant ligand pdgfb by endothelial cells in vitro and increased expression of pdgfb by arteries of zebrafish and mice in vivo. Additionally, we demonstrate that expression of the blood flow-regulated transcription factor klf2a in primitive veins negatively regulates cxcr4/cxcl12 and pdgfb expression, restricting vSMC recruitment to the arterial vasculature. Together, this signalling axis leads to the differential acquisition of vSMCs at sites where klf2a expression is low and both cxcr4a and pdgfb are co-expressed, i.e. arteries during early development.
684Cerebral venous thrombosis (CVT) is an uncommon form of cerebrovascular disease, with an incidence of three to four cases per million persons. Although acute-onset headache is the most consistent presentation, CVT may also manifest as seizures, intracranial hypertension, and focal sensorimotor deficits 1 . Here, we report the unusual development of subacute parkinsonism secondary to multiple cerebral sinus thromboses. CASE REPORTA 57-year-old right-handed woman with a three year history of diffuse, intermittent headaches presented to the Jewish General Hospital (Montreal) with worsening non-pulsatile headache and progressive hypophonia, micrographia, bradyphrenia and gait unsteadiness over a three week period. There were no complaints of hyposmia, sleep disturbances, constipation or other pre-motor symptoms of idiopathic Parkinson disease. Her past medical history was unremarkable and her medication list included vitamin D and calcium supplements only. Physical examination revealed normal vital signs with no evidence of postural hypotension, normal level of consciousness, orientation, attention, language, affect, judgment and insight. There was facial hypomimia but the rest of the cranial nerve exam, including bilateral olfactory nerve testing, was normal. There was marked hypophonia and micrographia and moderate bradykinesia and cogwheel rigidity. Muscle power was normal and tremor was absent. The gait was narrow-based, small-steppage and unsteady. There was severe retropulsion on pull-testing. Sensory, cerebellar and reflex testing was unremarkable save for prominent glabellar tap and palmomental signs.A computed tomogram (CT) scan of the head (Figure) showed small, scattered hyperdensities in bilateral frontal, temporal and parietal lobes and in the region of the interpeduncular cistern. The white matter appeared abnormally hypodense consistent with generalized edema (a1-a2). Magnetic resonance imaging axial FLAIR sequences showed heterogeneous hyperintense signal of the transverse sinuses (left, arrow) and congested peripheral veins (b1-b2). Axial FLAIR and T2 sequences showed diffuse, hyperintense signal of the periventricular and subcortical white matter and mild sulcal effacement (c1-c2). Magnetic resonance venography (MRV) demonstrated occlusion of the transverse sinuses and distal internal cerebral veins, minimal flow within the vein of Galen, and severely congested cortical and subcortical veins and straight sinus (d1-d2).Routine hematology, erythrocyte sedimentation rate and Despite intravenous heparin and a therapeutic partial thromboplastin time, there was abrupt clinical deterioration characterized by confusion, worsening gait and double incontinence. A repeat CT of the head was unchanged. A trial of intra-jugular tPA and mechanical venous sinus thrombectomy were unsuccessful due to "rock-hard" clot consolidation. The patient was started on warfarin and dexamethasone with gradual improvement of neurological status to near-admission levels. She was discharged to a rehabilitation hospital on warfa...
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