HDAC7 Activates IKK/NF-κB Signaling to Regulate Astrocyte-Mediated Inflammation

Abstract

Class IIa histone deacetylases (HDAC) have been shown to drive innate immune cell-mediated inflammation in the peripheral system, but their roles in cerebral inflammatory responses remain largely unknown. Here, we elucidate that HDAC7 is selectively elevated in lipopolysaccharide (LPS)-challenged astrocytes both in vivo and in vitro. We identify that HDAC7 binds to the inhibitory kappa B kinase (IKK) to promote IKKα and IKKβ deacetylation and subsequent activation, leading to the activation of nuclear factor κB (NF-κB). Astrocyte-specific overexpression of HDAC7 results in NF-κB activation, pro-inflammatory gene upregulation and anxiety-like behaviors in mice, while downregulating HDAC7 reserves LPS-induced NF-κB activation and inflammatory responses. Furthermore, pharmacological inhibition of HDAC7 by a class IIa HDAC inhibitor attenuates LPS-induced NF-κB activation, inflammatory responses and anxiety-like behaviors both in vivo and in vitro. Together, our data reveal a novel mechanism of HDAC7 in astrocyte-mediated inflammation and suggest that targeting HDAC7 could be a potential therapeutic strategy for the treatment of anxiety and other inflammation-related diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-022-02965-6.

IKKβ inhibits cognitive memory and adult hippocampal neurogenesis via the β-catenin pathway

“…These results suggest that IKKβ inhibits locomotion and hyperactivity, which is consistent with the reported reduction in locomotor activity in NF-κB p50-de cient mice [55]. However, increased NF-kB signaling in mice with constitutively active IKK2 expression [56] and HDAC7 overexpression [57] reduced mouse locomotion and activity, which is consistent with our results.…”

Quercetagitrin Inhibits Tau Accumulation and Reverses Neuroinflammation and Cognitive Deficits in P301S-Tau Transgenic Mice

“…Our results suggest that quercetagitrin treatment leads to attenuated hippocampal astro-and microgliosis, inhibited NF-κB signaling activation, and reduced the production of the inflammatory cytokines Il-1α and Il-6 in P301S-tau transgenic mice. NF-κB signaling activation is closely associated with neuroinflammation both in astrocytes and microglia, and it plays a critical role in the progression of tauopathy [11,18]. Quercetagitrin, isolated from the flowers of the African marigold (Tagetes erecta), has been reported to have an anti-inflammation effect in neutrophils [8,19].…”

“…Moreover, studies have indicated that quercetagetin, a similar flavonoid also derived from marigolds, could suppress NF-κB activation via the inhibition of c-Jun NH 2 -terminal kinases [20]. The inactivation of NF-κB signaling reduces astrogliosis, microgliosis, and inflammatory responses, and it protects against spatial memory deficits in WT and P301S-tau transgenic mice [11,18]. Thus, the reversed gliosis and inflammatory responses observed in P301S-tau transgenic mice might be attributable to the inhibitory effect of quercetagetin on NF-κB signaling.…”

HDACi: The Columbus’ Egg in Improving Cancer Treatment and Reducing Neurotoxicity?

“…For some of them, such as HDAC8, a role in neuronal differentiation has been suggested [ 64 ], while HDAC9 and HDAC11 activity has been related to neuronal survival, neurite elongation and axonal development [ 27 , 67 ]. The opposite effect has been suggested for HDAC10, which has been reported to block neuronal differentiation [ 68 ], while the expression of HDAC7 in astrocytes promoted inflammation through Nf-kB activation [ 69 ]. So far, however, only a few studies on these isozymes have been conducted, and new insights on the role of such HDACs would be necessary to understand their possible implication in the nervous system.…”