Abstract
Autophagy fights against harmful stimuli and degrades cytosolic macromolecules, organelles, and intracellular pathogens. Autophagy dysfunction is associated with many diseases, including infectious and inflammatory diseases. Recent studies have identified the critical role of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasomes activation in the innate immune system, which mediates the secretion of proinflammatory cytokines IL-1β/IL-18 and cleaves Gasdermin D to induce pyroptosis in response to pathogenic and sterile stimuli. Accumulating evidence has highlighted the crosstalk between autophagy and NLRP3 inflammasome in multifaceted ways to influence host defense and inflammation. However, the underlying mechanisms require further clarification. Histone deacetylase 6 (HDAC6) is a class IIb deacetylase among the 18 mammalian HDACs, which mainly localizes in the cytoplasm. It is involved in two functional deacetylase domains and a ubiquitin-binding zinc finger domain (ZnF-BUZ). Due to its unique structure, HDAC6 regulates various physiological processes, including autophagy and NLRP3 inflammasome, and may play a role in the crosstalk between them. In this review, we provide insight into the mechanisms by which HDAC6 regulates autophagy and NLRP3 inflammasome and we explored the possibility and challenges of HDAC6 in the crosstalk between autophagy and NLRP3 inflammasome. Finally, we discuss HDAC6 inhibitors as a potential therapeutic approach targeting either autophagy or NLRP3 inflammasome as an anti-inflammatory strategy, although further clarification is required regarding their crosstalk.
Highlights
Autophagy is a conservative mechanism for maintaining homeostasis in cells, which degrades misfolded proteins, damaged organelles, and intracellular pathogens [1]
There are no studies indicating that Histone deacetylase 6 (HDAC6) promotes autophagy to reduce the activation of NLRP3 inflammasomes directly, according to the current evidence, it is possible that HDAC6 participates in the autophagic degradation of the components of NLRP3 inflammasomes to regulate its activation
The crosstalk between autophagy and NLRP3 inflammasome is essential for host defense and the inflammatory response
Summary
Autophagy is a conservative mechanism for maintaining homeostasis in cells, which degrades misfolded proteins, damaged organelles, and intracellular pathogens [1]. HDAC6 has been reported to promote the expression of NF-kB to enhance the transcription of pro-IL1b, increase the release of IL-1b, and aggravate inflammation via the interaction of upstream activators of NF-kB, including myeloid differentiation primary response protein 88 (Myd88), a-tubulin, and ROS [93, 122, 123]. Yan et al reported that pharmacological inhibition of HDAC6 attenuates the expression of NLRP3 and mature caspase-1 and IL-1b, and protects dopaminergic neurons via Prx II acetylation, which reduces ROS production [26] These studies suggest that HDAC6 mediates the activation of NLRP3 inflammasome, probably through Prx I and Prx II deacetylation which upregulates ROS production. The effect of HDAC6 on the PTM of NLRP3 inflammasome is controversial, previous studies indicated that the HDAC6 ubiquitin-binding domain but not deacetylase activity, is required for NLRP3 activation
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