近日，荷兰拉德堡德大学Musa M. Mhlanga团队发现，一条染色质调控的双相回路协调IL-1β介导的炎症反应。相关论文于2023年12月13日在线发表于国际学术期刊《自然—遗传学》。

研究人员表示，炎症的特点是双相循环，最初由促炎阶段组成，随后由抗炎过程消解。白细胞介素-1β（IL-1β）是促炎症的主要调节因子，它与IL-37在同一拓扑关联域（TAD）中编码，而IL-37是一种抗炎细胞因子，能对抗IL-1β的功能。

在这个TAD中，研究人员发现了一种名为AMANZI的长非编码RNA，它通过诱导IL37转录来负向调节IL-1β的表达和训练免疫力。研究人员发现，IL37的激活是通过动态长程染色质接触的形成进行的，这种接触导致了抗炎反应的时间延迟。AMANZI中的常见变异体rs16944增强了这一调控回路，使个体倾向于增强促炎症反应或免疫抑制。这项研究揭示了一种染色质介导的双相回路，它能协调IL-1β和IL-37的表达，从而在单个TAD内调节两种功能相反的炎症状态。

附：英文原文

Title: A chromatin-regulated biphasic circuit coordinates IL-1β-mediated inflammation

Author: Fok, Ezio T., Moorlag, Simone J. C. F. M., Negishi, Yutaka, Groh, Laszlo A., dos Santos, Jssica Cristina, Grwe, Cathrin, Monge, Valerie Villacorta, Craenmehr, Daphne D. D., van Roosmalen, Mellanie, da Cunha Jolvino, David Pablo, Migliorini, Letcia Busato, Neto, Ary Serpa, Severino, Patricia, Vermeulen, Michiel, Joosten, Leo A. B., Netea, Mihai G., Fanucchi, Stephanie, Mhlanga, Musa M.

Issue&Volume: 2023-12-13

Abstract: Inflammation is characterized by a biphasic cycle consisting initially of a proinflammatory phase that is subsequently resolved by anti-inflammatory processes. Interleukin-1β (IL-1β) is a master regulator of proinflammation and is encoded within the same topologically associating domain (TAD) as IL-37, which is an anti-inflammatory cytokine that opposes the function of IL-1β. Within this TAD, we identified a long noncoding RNA called AMANZI, which negatively regulates IL-1β expression and trained immunity through the induction of IL37 transcription. We found that the activation of IL37 occurs through the formation of a dynamic long-range chromatin contact that leads to the temporal delay of anti-inflammatory responses. The common variant rs16944 present in AMANZI augments this regulatory circuit, predisposing individuals to enhanced proinflammation or immunosuppression. Our work illuminates a chromatin-mediated biphasic circuit coordinating expression of IL-1β and IL-37, thereby regulating two functionally opposed states of inflammation from within a single TAD.

DOI: 10.1038/s41588-023-01598-2

Source: https://www.nature.com/articles/s41588-023-01598-2