Abstract
BackgroundTwo activation states of reactive astrocytes termed A1 and A2 subtypes emerge at the lesion sites following spinal cord injury (SCI). A1 astrocytes are known to be neurotoxic that participate in neuropathogenesis, whereas A2 astrocytes have been assigned the neuroprotective activity. Heat shock transcription factor 1 (HSF1) plays roles in protecting cells from stress-induced apoptosis and in controlling inflammatory activation. It is unknown whether HSF1 is involved in suppressing the conversion of A1 astrocytes following SCI.MethodsA contusion model of the rat spinal cord was established, and the correlations between HSF1 expression and onset of A1 and A2 astrocytes were assayed by Western blot and immunohistochemistry. 17-AAG, the agonist of HSF1, was employed to treat the primary cultured astrocytes following a challenge by an A1-astrocyte-conditioned medium (ACM) containing 3 ng/ml of IL-1α, 30 ng/ml of TNF-α, and 400 ng/ml of C1q for induction of the A1 subtype. The effects of 17-AAG on the phenotype conversion of astrocytes, as well as underlying signal pathways, were examined by Western blot or immunohistochemistry.ResultsThe protein levels of HSF1 were significantly increased at 4 days and 7 days following rat SCI, showing colocalization with astrocytes. Meanwhile, C3-positive A1 astrocytes were observed to accumulate at lesion sites with a peak at 1 day and 4 days. Distinctively, the S100A10-positive A2 subtype reached its peak at 4 days and 7 days. Incubation of the primary astrocytes with ACM markedly induced the conversion of the A1 phenotype, whereas an addition of 17-AAG significantly suppressed such inducible effects without conversion of the A2 subtype. Activation of HSF1 remarkably inhibited the activities of MAPKs and NFκB, which was responsible for the regulation of C3 expression. Administration of 17-AAG at the lesion sites of rats was able to reduce the accumulation of A1 astrocytes.ConclusionCollectively, these data reveal a novel mechanism of astrocyte phenotype conversion following SCI, and HSF1 plays key roles in suppressing excessive increase of neurotoxic A1 astrocytes.
Highlights
Two activation states of reactive astrocytes termed A1 and A2 subtypes emerge at the lesion sites following spinal cord injury (SCI)
SCI-induced activation of Heat shock transcription factor 1 (HSF1) is correlated to the conversion of A1 and A2 astrocyte phenotypes To understand the correlations between HSF1 activation and conversion of reactive astrocyte states following SCI, injury-induced expression of HSF1 in the contused spinal cord was first determined
Longitudinal sections stained with glial fibrillary acid protein (GFAP) displayed that the number of Discussion Molecular screening studies have revealed that A1 and A2 subtype of reactive astrocytes are detectably expressed in various central nervous system (CNS) neurodegenerative disorders and injured spinal cord [4, 13, 41,42,43,44,45,46]
Summary
Two activation states of reactive astrocytes termed A1 and A2 subtypes emerge at the lesion sites following spinal cord injury (SCI). Heat shock transcription factor 1 (HSF1) plays roles in protecting cells from stress-induced apoptosis and in controlling inflammatory activation It is unknown whether HSF1 is involved in suppressing the conversion of A1 astrocytes following SCI. A1 astrocytes have been found to release neurotoxic factors such as complement components and inflammatory cytokines to mediate the death of neurons and oligodendrocytes, thereby contributing to the progression of neuropathology [7, 8] They are shown to participate in a variety of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis [6]. Ischemia-induced A2 astrocytes displayed neuroprotective functions by producing anti-inflammatory cytokines and neurotrophic factors [4, 7, 9, 10]. The temporal-spatial conversion of the two states of astrocytes and the underlying regulatory mechanisms are not fully elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
