Glia
-
Neurosteroids are synthesized either by glial cells, by neurons, or within the context of neuron-glia cross-talk. Various studies suggested neurosteroid involvement in the control of neurodegeneration but there is no evidence showing that the natural protection of nerve cells against apoptosis directly depends on their own capacity to produce neuroprotective neurosteroids. Here, we investigated the interactions between neurosteroidogenesis and apoptosis occurring in sensory structures of rats subjected to neuropathic pain generated by sciatic nerve chronic constriction injury (CCI). ⋯ Consistently, immunohistochemical investigations localized aromatase (estradiol-synthesizing enzyme) in DRG neurons but not in SGC. Pharmacological inhibition of aromatase caused apoptosis of CCI rat DRG neurons. Altogether, our results suggest that endogenously produced neurosteroids such as estradiol may be pivotal for the protection of DRG sensory neurons against sciatic nerve CCI-induced apoptosis.
-
Cathepsin B (CB) is a cysteine lysosomal protease implicated in a number of inflammatory diseases. Although it is now evident that caspase-1, an essential enzyme for maturation of interleukin-1beta (IL-1beta), can be activated through the inflammasome, there is still evidence suggesting the existence of lysosomal-proinflammatory caspase pathways. In the present study, a marked induction of pro-IL-1beta, its processing to the mature form and secretion were observed in the primary cultured microglia prepared from wild-type mice after stimulation with chromogranin A (CGA). ⋯ Inconsistent with these in vitro observations, the immunoreactivity for the cleaved IL-1beta was markedly observed in microglia of the hippocampus from aged wild-type but not CB-deficient mice. These observations strongly suggest that CB plays a key role in the pro-IL-1beta maturation through the caspase-1 activation in enlarged lysosomes of CGA-treated microglia. Therefore, either pharmacological or genetic inhibition of CB may provide therapeutic intervention in inflammation-associated neurological diseases.
-
Interleukin (IL)-1beta has been shown to induce matrix metalloproteinase (MMP)-9 expression through mitogen-activated protein kinases, including JNK, in rat brain astrocyte-1 (RBA-1) cells. However, little is known about whether JNK activated by Ca(2+)-dependent CaMKII is associated with MMP-9 expression induced by IL-1beta. Here, we report that the Ca(2+)/CaMKII/JNK/c-Jun participates in the MMP-9 expression induced by IL-1beta. ⋯ The activation and recruitment of c-Jun to MMP-9 promoter were inhibited by pretreatment with BAPTA, TG, KN-62, or SP600125. Moreover, IL-1beta-induced MMP-9 gene transcription by AP-1 was confirmed by transfection with a MMP-9 promoter-luciferase reporter plasmid with a distal AP-1-binding site (-511 to -497 bp) adjacent to an Ets-binding site-mutation (mt-AP1/Ets-MMP-9). These results demonstrated that in RBA-1 cells, JNK/c-Jun activation was mediated through a Ca(2+)-dependent CaMKII pathway that promoted transcription factor c-Jun/AP-1 recruitment and eventually led to increase in MMP-9 expression by IL-1beta.
-
We previously demonstrated that coadministration of glial cell line-derived neurotrophic factor (GDNF) with grafts of Schwann cells (SCs) enhanced axonal regeneration and remyelination following spinal cord injury (SCI). However, the cellular target through which GDNF mediates such actions was unclear. Here, we report that GDNF enhanced both the number and caliber of regenerated axons in vivo and increased neurite outgrowth of dorsal root ganglion neurons (DRGN) in vitro, suggesting that GDNF has a direct effect on neurons. ⋯ GDNF increased the expression of the 140 kDa neural cell adhesion molecule (NCAM) in isolated SCs but not their expression of the adhesion molecule L1 or the secretion of the neurotrophins NGF, NT3, or BDNF. Overall, these results support the hypothesis that GDNF-enhanced axonal regeneration and SC myelination is mediated mainly through a direct effect of GDNF on neurons. They also suggest that the combination of GDNF administration and SC transplantation may represent an effective strategy to promote axonal regeneration and myelin formation after injury in the spinal cord.
-
Microglia provide surveillance in the central nervous system and become activated following tissue insult. Detailed mechanisms by which microglia detect and respond to their environment are not fully understood, but it is known that microglia express a number of surface receptors and ion channels, including voltage-gated sodium channels, that participate in transduction of external stimuli to intra-cellular responses. To determine whether activated microglia are affected by the activity of sodium channels, we examined the expression of sodium channel isoforms in cultured microglia and the action of sodium channel blockade on multiple functions of activated microglia. ⋯ TTX (0.3 microM) reduced, but to a smaller extent, the release of IL-1 alpha, IL-1 beta, and TNF-alpha from activated microglia. Phenytoin and TTX also significantly decreased by approximately 50% adenosine triphosphate-induced migration by microglia; studies with microglia cultured from med mice (which lack Nav1.6) indicate that Nav1.6 plays a role in microglial migration. The results demonstrate that the activity of sodium channels contributes to effector roles of activated microglia.