Rajiv Leon | UCLA Extension (original) (raw)
Papers by Rajiv Leon
Proceedings of The National Academy of Sciences, 2003
Innate immunity is an evolutionarily ancient system that provides organisms with immediately avai... more Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration. microglia ͉ neuronal injury ͉ lipopolysaccharide ͉ infection RT-PCR. Relative levels of TLR4 and CD14 mRNA in neurons and microglia were determined by RT-PCR as described (16).
American Journal of Otolaryngology, 1996
Journal of Neurobiology, 2004
Neurons of the peripheral nervous system are capable of extensive regeneration following axonal i... more Neurons of the peripheral nervous system are capable of extensive regeneration following axonal injury. This regenerative response is accompanied by changes in gene expression in axotomized neurons and associated nonneuronal cells. In the sympathetic nervous system, a few of the genes affected by axonal injury have been identified; however, a broad sampling of genes that could reveal additional and unexpected changes in expression has been lacking. We have used DNA microarray technology to study changes in gene expression within 48 h of transecting the postganglionic trunks of the adult rat superior cervical ganglion (SCG). The expression of more than 200 known genes changed in the ganglion, most of these being genes not previously associated with the response to injury. In contrast, only 10 genes changed following transection of the preganglionic cervical sympathetic trunk. Real-time RT-PCR analysis verified the upregulation of a number of the axotomy-induced genes, including activating tran-scription factor-3 (ATF-3), arginase I (arg I), cardiac ankyrin repeat protein, galanin, osteopontin, pituitary adenylate cyclase-activating polypeptide (PACAP), parathyroid hormone-related peptide, and UDP-glucoronosyltransferase. Arg I mRNA and protein were shown to increase within neurons of the axotomized SCG. Furthermore, increases in the levels of putrescine and spermidine, a diamine and polyamine produced downstream of arg I activity, were also detected in the axotomized SCG. Our results identified many candidate genes to be studied in the context of peripheral nerve regeneration. In addition, the data suggest a potential role for putrescine and spermidine, acting downstream of arg I, in the regenerative process.
Proceedings of The National Academy of Sciences, 2003
Innate immunity is an evolutionarily ancient system that provides organisms with immediately avai... more Innate immunity is an evolutionarily ancient system that provides organisms with immediately available defense mechanisms through recognition of pathogen-associated molecular patterns. We show that in the CNS, specific activation of innate immunity through a Toll-like receptor 4 (TLR4)-dependent pathway leads to neurodegeneration. We identify microglia as the major lipopolysaccharide (LPS)-responsive cell in the CNS. TLR4 activation leads to extensive neuronal death in vitro that depends on the presence of microglia. LPS leads to dramatic neuronal loss in cultures prepared from wild-type mice but does not induce neuronal injury in CNS cultures derived from tlr4 mutant mice. In an in vivo model of neurodegeneration, stimulating the innate immune response with LPS converts a subthreshold hypoxic-ischemic insult from no discernable neuronal injury to severe axonal and neuronal loss. In contrast, animals bearing a loss-of-function mutation in the tlr4 gene are resistant to neuronal injury in the same model. The present study demonstrates a mechanistic link among innate immunity, TLRs, and neurodegeneration. microglia ͉ neuronal injury ͉ lipopolysaccharide ͉ infection RT-PCR. Relative levels of TLR4 and CD14 mRNA in neurons and microglia were determined by RT-PCR as described (16).
American Journal of Otolaryngology, 1996
Journal of Neurobiology, 2004
Neurons of the peripheral nervous system are capable of extensive regeneration following axonal i... more Neurons of the peripheral nervous system are capable of extensive regeneration following axonal injury. This regenerative response is accompanied by changes in gene expression in axotomized neurons and associated nonneuronal cells. In the sympathetic nervous system, a few of the genes affected by axonal injury have been identified; however, a broad sampling of genes that could reveal additional and unexpected changes in expression has been lacking. We have used DNA microarray technology to study changes in gene expression within 48 h of transecting the postganglionic trunks of the adult rat superior cervical ganglion (SCG). The expression of more than 200 known genes changed in the ganglion, most of these being genes not previously associated with the response to injury. In contrast, only 10 genes changed following transection of the preganglionic cervical sympathetic trunk. Real-time RT-PCR analysis verified the upregulation of a number of the axotomy-induced genes, including activating tran-scription factor-3 (ATF-3), arginase I (arg I), cardiac ankyrin repeat protein, galanin, osteopontin, pituitary adenylate cyclase-activating polypeptide (PACAP), parathyroid hormone-related peptide, and UDP-glucoronosyltransferase. Arg I mRNA and protein were shown to increase within neurons of the axotomized SCG. Furthermore, increases in the levels of putrescine and spermidine, a diamine and polyamine produced downstream of arg I activity, were also detected in the axotomized SCG. Our results identified many candidate genes to be studied in the context of peripheral nerve regeneration. In addition, the data suggest a potential role for putrescine and spermidine, acting downstream of arg I, in the regenerative process.