The Role of HDAC6 in Autophagy and NLRP3 Inflammasome

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.

Histone Deacetylase 6 Inhibitor CKD-WID Suppressed Monosodium Urate-Induced Osteoclast Formation by Blocking Calcineurin-NFAT Pathway in RAW 264.7 Cells

“…The possibility that HDACs are involved in the osteoclast formation in the pathogenesis of gout has been proposed. HDAC6 inhibition suppressed NLRP3 inflammasome activation by attenuating the transcription of NF-κB in the priming process and by reducing the expression of mature caspase-1, ultimately resulting in reduced production of IL-1β [ 17 ]. Cleophas et al showed that the HDAC1/2 inhibitor Romidepsin potently decreased the production of numerous inflammatory cytokines including IL-1β, IL1Ra, IL-6, and IL-8 in PBMCs incubated with MSU and palmitic acid, suggesting HDAC1/2 inhibition as a novel therapeutic strategy in acute gout [ 18 ].…”

“…Studies have shown that HDAC6 is involved in the activation of the NACHT, LRR, and PYD-domains-containing the protein 3 (NLRP3) inflammasome, playing an important role in the pathological mechanism of gout [ 17 ]. In addition, HDAC1/2 dual inhibition was shown to be an effective strategy in treating gout [ 18 ].…”

Cannabinoid receptor-2 attenuates neuroinflammation by promoting autophagy-mediated degradation of the NLRP3 inflammasome post spinal cord injury

“…Numerous mechanisms have been proposed to explain the interactions between the NLRP3 inflammasome and autophagy, including autophagy activation by inflammatory signaling via limited IL-1b production and targeting ubiquitinated inflammasomes (13). In neurological diseases, non-coding RNA, bio-enzymes, and small molecular compounds have been implicated in the interplay between ubiquitination and autophagy of NLRP3 (46)(47)(48). In LPSstimulated microglia, CB2R activation decreased NLRP3 expression associated with formation of autophagosomes, resulting in accumulation of LC3B and exhaustion of p62.…”

Reserpine maintains photoreceptor survival in retinal ciliopathy by resolving proteostasis imbalance and ciliogenesis defects

“…Our observation of high OFD1 levels in patient organoids compared to the control, despite an elevated autophagic flux, suggests alternative mechanisms. HDAC6 has also been demonstrated to promote autophagosome maturation ( 108, 109 ) as well as deacetylate microtubules to impede intracellular trafficking, which is a key driver of primary cilium disassembly. Higher expression of HDAC6 in patient organoids could explain both the failure of docking of pre-ciliary vesicles ( 33 ) and elevated autophagic flux in patient photoreceptors.…”