组蛋白去乙酰化酶HDAC3对NLRP3炎症小体活化以及相关炎症性疾病的调控与机制研究

Reciprocal interactions between the metabolic system and immune cells have been increasingly reported to play pivotal roles in both metabolic balance and immune homeostasis. Dysfunction of NLRP3 inflammasome is closely associated with the pathogenesis of diverse inflammatory diseases, but the underlying mechanisms are still unclear. The activation of bile acid-mediated signaling has been linked to improvement in metabolic syndromes and enhanced control of inflammation. Activation of the NLRP3 inflammasome triggers the caspase-1-dependent maturation and release of several pro-inflammatory cytokines, including interleukin-1β (IL-1β) and IL-18. Excessive activation of the inflammasome is therefore involved in the pathogenesis of several inflammatory disorders, including type-2 diabetes (T2D), atherosclerosis, gout, and Alzheimer’s disease, suggesting that this activation needs to be tightly controlled. Here we demonstrate that knockdown and inhibitor of histone deacetylatase HDAC3 specifically inhibit NLRP3 inflammasome activation and related caspase-1 activation, IL-1β secretion. Further, whether HDAC3 is involved in the activation of NLRP3 inflammasome still needs to be investigated. In light of our study, targeting HDAC3 may lead to new insights and treatments for NLRP3 inflammasome-related diseases.

研究表明，机体的免疫系统与代谢系统之间的相互作用对于维持机体代谢平衡和免疫稳态起着重要的调节作用。NLRP3炎症小体活化的失调与多种炎症性疾病以及代谢综合征的发生发展密切相关，寻找NLRP3炎症小体的内源性调控分子并阐明其作用机制有助于预防和治疗NLRP3相关疾病。通过前期药物筛选试验发现，组蛋白去乙酰化酶HDAC3抑制剂及敲除可以显著抑制NLRP3炎症小体的活化，包括pro-capsase-1和pro-IL-1的切割成熟等。近期研究报道HDAC3对代谢平衡具有重要的调控作用，然而其能否通过调控NLRP3炎症小体的活化，进而发挥其免疫调节作用并影响NLRP3相关炎症性疾病发生发展仍有待探究。为此我们拟在前期研究基础上利用一系列体内外实验进一步探究HDAC3调控NLRP3炎症小体活化和相关疾病发生的作用机制，为NLRP3相关疾病的靶向干预治疗及药物开发提供理论基础和实验依据。

研究表明，机体的免疫系统与代谢系统之间的相互作用对于维持机体代谢平衡和免疫稳态起着重要的调节作用。NLRP3炎症小体活化的失调与多种炎症性疾病以及代谢综合征的发生发展密切相关，寻找NLRP3炎症小体的内源性调控分子并阐明其作用机制有助于预防和治疗NLRP3相关疾病。通过前期药物筛选试验发现，组蛋白去乙酰化酶HDAC3抑制剂及敲除可以显著抑制NLRP3炎症小体的活化，包括pro-capsase-1和pro-IL-1的切割成熟等。近期研究报道HDAC3对代谢平衡具有重要的调控作用，然而其能否通过调控NLRP3炎症小体的活化，进而发挥其免疫调节作用并影响NLRP3相关炎症性疾病发生发展仍有待探究。为此我们拟在前期研究基础上利用一系列体内外实验进一步探究HDAC3调控NLRP3炎症小体活化和相关疾病发生的作用机制，为NLRP3相关疾病的靶向干预治疗及药物开发提供理论基础和实验依据。