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Dyad of CD40/CD40 Ligand Fosters Neuroinflammation at the Blood-Brain Barrier and Is Regulated via JNK Signaling: Implications for HIV-1 Encephalitis

Departments of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 07/2010; 30(28):9454-64. DOI: 10.1523/JNEUROSCI.5796-09.2010
Source: PubMed

ABSTRACT Human immunodeficiency virus 1 (HIV-1) infection may result in activation of peripheral monocytes followed by their infiltration into the CNS, where the release of proinflammatory mediators causes neurologic disease. Previously, we detected high levels of soluble CD40 ligand (CD40L) in CSF and plasma of HIV-infected patients with cognitive impairment. We now show that CD40, a receptor for CD40L, is highly expressed in brain endothelial cells of patients affected by HIV-1 encephalitis (HIVE), suggesting an important role for the CD40/CD40L dyad in regulating blood-brain barrier (BBB) functions. This concept was further supported by in vitro experiments. Exposure of primary human brain microvascular endothelial cells (BMVECs) to CD40L upregulated the expression of adhesion molecules intracellular adhesion molecule-1 and vascular cell adhesion molecule-1, which caused a fourfold increase in monocyte adhesion to BMVECs and stimulated migration across an in vitro BBB model. Investigations into the intracellular signaling pathways that govern these events revealed that cJUN-N-terminal kinase (JNK) is critical to CD40 activation in the BMVECs. CD40L induced activation of mixed-lineage-kinase-3 and JNK, leading to the subsequent activation of cJUN/AP-1 (activating-protein-1). JNK inhibition in the BMVECs prevented CD40L-mediated induction of adhesion molecules, monocyte adhesion, and transendothelial migration. These new findings support the concept that the CD40/CD40L dyad plays an important role in HIVE neuroinflammation.

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    • "The roles of the CD40/CD154 dyad in several autoimmune diseases have been studied by several independent groups [12] [15] [18] [21] [24], whereas the role of these interactions in MS remains largely unknown. In the present matched caseecontrol study, we attempted to focus on the relation between the expression of MMP-9, MMP-2, and TIMP-1 and change in the concentrations of both isoforms of CD154 in MS patients and healthy controls. "
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    • "ConsideringtheupregulationofadhesionmoleculesonBMVECs inresponsetoexcesssCD40LreportedbyRamirezetal.(2010),it islikelythattheabsenceofCD40Lsignalingintheseanimalsalters adhesionmoleculeupregulationinresponsetoHIV-associated effectormolecules,therebyreducingtheattachmentandsubsequentextravasationofleukocytesthroughBMVECs .Thus, whileotherpro-inflammatorymoleculesinadditiontosCD40L areundoubtedlyplayingaroleinactivationandincreased permeabilityoftheBBB,inhibitingCD40/CD40Lsignaling mayprovetobeabeneficialpointofinterventioninthe pathogenesisofHAND. "
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