HSF1 is involved in suppressing A1 phenotype conversion of astrocytes following spinal cord injury in rats

Abstract

Background Two 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. Methods A 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. Results The 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. Conclusion Collectively, 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.

Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy

“…Epidermal growth factor-containing hydrogels can reportedly alter astrocyte behavior, i.e., they downregulate the expression of deleterious neurotoxicity-related genes ( Fbln5 and Rt1-S3 ) while upregulating that of potentially beneficial neuroprotective phenotype-associated genes ( Clcf1 , Tgm1 , and Ptgs2 ), thereby indirectly enhancing neuroprotection and neuroplasticity (Chan et al, 2019 ). RTMS, HSF1, and physical exercise also lead to the conversion of the neurotoxic phenotype into the neuroprotective phenotype, which promotes functional recovery after injury (Zong et al, 2020 ; Jiang et al, 2021 ; Li L. et al, 2021 ). Mitochondria may also play a role in A1 polarization.…”

The role of immune cells and associated immunological factors in the immune response to spinal cord injury

“…In the same year, in another study, Li et al. demonstrated that heat shock transcription factor 1 plays a key role in suppressing the excessive increase in neurotoxic A1 astrocytes ( 41 ). Wang et al.…”

“…In 2021, Zhang et al found that miR-21a-5p can aggravate the inflammatory response after traumatic SCI by increasing A1 polarization via the inhibition of the CNTF/ STAT3/Nkrf signaling pathway (40). In the same year, in another study, Li et al demonstrated that heat shock transcription factor 1 plays a key role in suppressing the excessive increase in neurotoxic A1 astrocytes (41). Wang et al showed that the transformation of A1/A2 reactive astrocytes may be associated with functional recovery after SCI (42).…”

A Novel Progress: Glial Cells and Inflammatory Pain

“…HSF1 regulates NF-κB activity by inhibiting the nuclear binding activity of NF-κB or decreasing the degradation of IκB protein. It binds to promoters to inhibit TNF-α and IL-1β expression, ultimately down-regulating the transformation of A1 astrocytes . Promoting the conversion of the A1 subtype to the A2 subtype can effectively suppress inflammation.…”

“…54 Astrocytes have been shown to have two subtypes, A1 and A2. A1 astrocytes are induced by cytokines such as IL-1α and 58 Promoting the conversion of the A1 subtype to the A2 subtype can effectively suppress inflammation. Melatonin reduces the number of A1 astrocytes and increases the number of A2 astrocytes through the melatonin receptor 1A (MT1)/JAK2/STAT3 pathway and regulates the transformation of astrocytes from A1 subtype to A2 subtype.…”