德国亥姆霍兹协会马克斯·德尔布吕克分子医学中心Thomas Blankenstein研究小组发现干扰素-γ（IFNγ）与细胞外基质结合可防止致命的全身毒性。这一研究成果于2023年2月2日在线发表在国际学术期刊《自然—免疫学》上。

研究人员表示，IFNγ是细胞免疫应答的重要中介，但这种细胞因子的全身性高水平与免疫病理相关。通过其正电荷C端氨基酸（KRKR）、ECM结合域（EBD），IFNγ结合到它的受体（IFNγR）和细胞外基质（ECM）。在演化过程中，IFNγ并不是很保守，但EBD高度保守，这表明它具有关键功能。

研究人员发现缺乏EBD的IFNγ（IFNγΔKRKR）不与ECM结合，但仍与IFNγR结合并保持生物活性。IFNγΔKRKR在肿瘤中的过表达减少了局部ECM结合，增加了全身水平，并引起了疾病行为、体重减轻和毒性。为了分析EBD在感染过程中的功能，研究人员通过CRISPR-Cas9产生了缺少EBD的IFNγΔKRKR小鼠。感染淋巴细胞性脉络丛脑膜炎病毒会导致更高的系统IFNγΔKRKR水平、增强的疾病行为、体重减轻和致命毒性。研究人员得出结论，IFNγ的局部滞留是一个关键机制，可用于保护机体免受系统毒性在长时间的免疫刺激。

附：英文原文

Title: IFNγ binding to extracellular matrix prevents fatal systemic toxicity

Author: Kemna, Josephine, Gout, Evelyne, Daniau, Leon, Lao, Jessica, Weiert, Kristoffer, Ammann, Sandra, Khn, Ralf, Richter, Matthias, Molenda, Christine, Sporbert, Anje, Zocholl, Dario, Klopfleisch, Robert, Lortat-Jacob, Hugues, Aichele, Peter, Kammertoens, Thomas, Blankenstein, Thomas

Issue&Volume: 2023-02-02

Abstract: Interferon-γ (IFNγ) is an important mediator of cellular immune responses, but high systemic levels of this cytokine are associated with immunopathology. IFNγ binds to its receptor (IFNγR) and to extracellular matrix (ECM) via four positively charged C-terminal amino acids (KRKR), the ECM-binding domain (EBD). Across evolution, IFNγ is not well conserved, but the EBD is highly conserved, suggesting a critical function. Here, we show that IFNγ lacking the EBD (IFNγΔKRKR) does not bind to ECM but still binds to the IFNγR and retains bioactivity. Overexpression of IFNγΔKRKR in tumors reduced local ECM binding, increased systemic levels and induced sickness behavior, weight loss and toxicity. To analyze the function of the EBD during infection, we generated IFNγΔKRKR mice lacking the EBD by using CRISPR–Cas9. Infection with lymphocytic choriomeningitis virus resulted in higher systemic IFNγΔKRKR levels, enhanced sickness behavior, weight loss and fatal toxicity. We conclude that local retention of IFNγ is a pivotal mechanism to protect the organism from systemic toxicity during prolonged immune stimulation.

DOI: 10.1038/s41590-023-01420-5

Source: https://www.nature.com/articles/s41590-023-01420-5