Proteolytic processing of SDF-1alpha reveals a change in receptor specificity mediating HIV-associated neurodegeneration.
Proteolytic cleavage of constitutively expressed proteins can generate peptides with novel bioactive properties. Matrix metalloproteinase (MMP)-2 cleaves the 4 amino-terminal residues of the chemokine, stromal cell-derived factor (SDF)-1alpha, yielding a highly neurotoxic molecule, SDF(5-67), which fails to bind to its cognate receptor, CXCR4. Herein, we detected SDF(5-67) in brain monocytoid cells of HIV-infected persons, particularly in those with HIV-associated dementia. SDF(5-67) activated cell type-specific expression of proinflammatory genes including IL-1beta, TNFalpha, indoleamine 2',3'-dioxygenase (IDO), and IL-10 in both astrocytic and monocytoid cells (P < 0.05). Unlike SDF-1alpha, SDF(5-67) caused neuronal membrane perturbations with ensuing neurotoxicity and apoptosis (P < 0.05) through engagement of an inducible receptor. CXCR3 antagonists and siRNA-mediated knockdown of CXCR3 inhibited SDF(5-67)-stimulated neurophysiological changes, neuronal death, and neuroimmune activation (P < 0.05). Moreover SDF(5-67) bound directly to CXCR3 in a competitive manner, mediated by its amino terminus. In vivo neuroinflammation, neuronal loss, and neurobehavioral abnormalities caused by SDF(5-67) (P < 0.05) were prevented by a CXCR3 antagonist. These studies reveal additive neuropathogenic properties exerted by a proteolytically cleaved chemokine as consequences of a change in receptor specificity, culminating in neurodegeneration.
Vergote
David
D
Department of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2S2.
Butler
Georgina S
GS
Ooms
Martine
M
Cox
Jennifer H
JH
Silva
Claudia
C
Hollenberg
Morley D
MD
Jhamandas
Jack H
JH
Overall
Christopher M
CM
Power
Christopher
C
D000818:Animals; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism*; D004594:Electrophysiology; D015658:HIV Infections / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009410:Nerve Degeneration / Q000150:complications / Q000378:metabolism* / Q000473:pathology* / Q000821:virology; D018408:Patch-Clamp Techniques; D051381:Rats; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000378:metabolism*
C515255:CXCL12 protein, human; C515187:CXCR3 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515189:Cxcr3 protein, rat; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine