New Drug Incubator Department, Italfarmaco Group, Cinisello Balsamo, Italy.
Department of Experimental Oncology, IEO European Institute of Oncology IRCCS, Milan, Italy.
Front Immunol. 2022 May 3;13:841716. doi: 10.3389/fimmu.2022.841716. eCollection 2022.
The COVID-19 pandemic has had a devastating impact worldwide and has been a great challenge for the scientific community. Vaccines against SARS-CoV-2 are now efficiently lessening COVID-19 mortality, although finding a cure for this infection is still a priority. An unbalanced immune response and the uncontrolled release of proinflammatory cytokines are features of COVID-19 pathophysiology and contribute to disease progression and worsening. Histone deacetylases (HDACs) have gained interest in immunology, as they regulate the innate and adaptative immune response at different levels. Inhibitors of these enzymes have already proven therapeutic potential in cancer and are currently being investigated for the treatment of autoimmune diseases. We thus tested the effects of different HDAC inhibitors, with a focus on a selective HDAC6 inhibitor, on immune and epithelial cells in models that mimic cells activation after viral infection. Our data indicate that HDAC inhibitors reduce cytokines release by airway epithelial cells, monocytes and macrophages. This anti-inflammatory effect occurs together with the reduction of monocytes activation and T cell exhaustion and with an increase of T cell differentiation towards a T central memory phenotype. Moreover, HDAC inhibitors hinder IFN-I expression and downstream effects in both airway epithelial cells and immune cells, thus potentially counteracting the negative effects promoted in critical COVID-19 patients by the late or persistent IFN-I pathway activation. All these data suggest that an epigenetic therapeutic approach based on HDAC inhibitors represents a promising pharmacological treatment for severe COVID-19 patients.
新型冠状病毒肺炎（COVID-19）疫情在全球范围内造成了毁灭性的影响，对科学界来说是一个巨大的挑战。针对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）的疫苗现在可有效降低 COVID-19 的死亡率，尽管寻找针对这种感染的治愈方法仍然是当务之急。免疫反应失衡和促炎细胞因子的失控释放是 COVID-19 病理生理学的特征，并导致疾病进展和恶化。组蛋白去乙酰化酶（HDACs）在免疫学中受到关注，因为它们在不同水平上调节先天和适应性免疫反应。这些酶的抑制剂已在癌症治疗中证明具有治疗潜力，目前正在研究其用于治疗自身免疫性疾病。因此，我们测试了不同 HDAC 抑制剂对模拟病毒感染后细胞激活的模型中的免疫细胞和上皮细胞的作用，重点是选择性 HDAC6 抑制剂。我们的数据表明，HDAC 抑制剂可减少气道上皮细胞、单核细胞和巨噬细胞释放细胞因子。这种抗炎作用与单核细胞激活和 T 细胞耗竭减少以及 T 细胞向中央记忆表型分化增加同时发生。此外，HDAC 抑制剂还可阻碍气道上皮细胞和免疫细胞中 IFN-I 的表达及其下游效应，从而可能抵消严重 COVID-19 患者中由 IFN-I 途径晚期或持续激活引起的负面影响。所有这些数据表明，基于 HDAC 抑制剂的表观遗传治疗方法代表了严重 COVID-19 患者的一种有前途的药物治疗方法。
