慢性炎症相关疾病通常伴有极化的髓系抑制细胞介导的免疫抑制。慢性炎症（肿瘤相关和非相关）环境可能影响了表观遗传修饰的变化，从而影响了髓系抑制细胞的极化。项目目标是探讨肿瘤与非肿瘤环境中表观遗传修饰对慢性炎症髓系抑制细胞极化的调控作用。强调以下目的：1）分析肿瘤相关与肿瘤非相关的慢性炎症髓系抑制细胞，进一步确定炎症因子INF-α和IL-6在髓系抑制细胞极化过程中的作用；2）确定在慢性炎症髓系抑制细胞极化过程中甲基化组蛋白表观遗传修饰特征；3）确定在慢性炎症髓系抑制细胞极化过程中关键甲基化组蛋白转移酶与去甲基化酶及相关成分；4）决定慢性炎症髓系抑制细胞极化信号及相关非编码RNA对表观遗传组蛋白甲基化转移酶与去甲基化酶及相关复合物的调控机理；5）对已鉴定的表观遗传修饰相关因素进行评估，评价其对炎症髓系抑制细胞的极化以及疾病发展的影响。研究结果将为发展新的免疫治疗策略奠定坚实的基础。

Chronic inflammation typical to various diseases is associated with immunosuppression, mediated primarily by immature myeloid derived suppressor cells (MDSCs). Despite the rapid advances made in understanding MDSC biology, the molecular basis for their differentiation arrest, expansion, activation towards polarized MDSCs, are not yet fully explored. Studies found that pro-inflammatory cytokine TNF-α and IL6 are critical for MDSC polarization under chronic inflammatory environments, together with our preliminary results pointing at the possible.involvement of unique epigenetic changes as histone modifications and involvement of LNCRNAs via chromatin remodeling in response to different environments, led us to hypothesize that a complex milieu of epigenetic changes could sense the emerging chronic inflammatory environment typical to cancerous and non-cancerous pathologies and regulate MDSC polarization that lead to immunosuppression associated with complications and disease progression. Therefore, our general objective is to explore the mechanisms underlying the linkage between epigenetic modification, chronic inflammation and MDSC polarization that could lead us to the development of epigenetic.intervention modalities to increase immune potency and disease regression. More specifically we aim to: 1) Characterize polarized MDSC under chronic inflammatory conditions; non-cancerous [ulcerative colitis (UC) a form of inflammatory bowel disease (IBD)] and cancerous [colorectal.cancer (CRC)] and define the impacts of TNF-α and IL-6, 2) Characterize the epigenetic marks of histone modifications and associated genes critical in MDSC polarization and suppressive function, 3) Identify the methyltransferase (s) and/or demethylase (s) that play a critical role in the polarizing MDSCs, 4) Determine the mechanisms controlling expression and activity of the methyltransferase(s) and/or demethylase (s) involved in MDSC polarization, and 5) Assess the effect of “epigenetic treatments” on MDSC polarization and disease stage. Our results are expected to highlight the epigenetic modifications playing a role in MDSC polarization and immunosuppressive features during pathologies characterized by chronic inflammation and enable defining the critical roles of TNF-α and IL6 in these processes, which is expected to form a.solid ground for the development of new potential strategies towards recuperation of the host’s suppressed immune system and disease regression expected to highlight the epigenetic modifications playing a role in MDSC polarization and immunosuppressive features during pathologies characterized by chronic inflammation and enable defining the critical roles of TNF-α and IL6 in these processes, which is expected to form a solid ground for the development of new potential strategies towards recuperation of the host’s suppressed immune system and disease regression.

项目的背景、主要研究内容: 研究显示髓系抑制细胞在免疫系统中发挥关键调节作用。有关髓系抑制细胞的免疫生物学基础研究、与疾病发生发展以及疾病治疗的应用性研究是当今免疫学领域的研究焦点之一。尽管人们在过去十年在髓系抑制细胞的特征和临床意义研究方面取得了巨大进步，但是关于髓系抑制细胞极化的分子机理才刚刚起步。该项目将决定TNF-α和IL-6相关慢性炎症髓系抑制细胞的表观遗传修饰特征，重点关注甲基化组蛋白如H3K4me3, H3K27me3, H3K9me3和H3K36me3的修饰，鉴定髓系抑制细胞极化过程中关键的组蛋白甲基化转移酶、去甲基化酶及相关表观遗传调控因素，解析TNF-α和IL-6信号对表观遗传调控的机理，同时探讨慢性炎症髓系抑制细胞相关非编码RNA对表观遗传调控的机理。重要结果、关键数据:1) 鉴定了几条新lncRNA: 发现LNC-MDSC 能够与转录因子c/EBPbeta和表观遗传调控因素WDR5结合调控髓系抑制细胞分化和功能(Nature communication under review);也发现LNC-CHOP通过转录因子CHOP调控髓系抑制细胞 (Journal of Immunology under review)；发现LNC-RNCR3能够调控CHOP表达，文章已发表在oncotarget; 其他几个lncRNA研究在进行中。2) 发现了表观遗传调控因素新的调控机理。表观遗传调控因素p66能够调节STAT3的磷酸化和泛素化。文章已发表在 Journal of Immunology和 J Theor Bio.3) 鉴定了几个能够调节髓系抑制细胞分化和功能的miRNAs. 文章发表在J.leukoc Biol, plos one，Onco Targets Ther 和 molecular Immunology.4) 同时，对髓系抑制细胞的相关功能进行了研究， 文章发表在cell 子刊 Cell Reports, Scientific Reports 和 Nature communications.这些成果不仅为阐明髓系抑制细胞分化的表观遗传调控机理提供依据，也将对相关重大疾病的治疗和预防产生重要影响，为后续开展免疫生物治疗研究提供新的科学依据、新思路和新技术。