美国斯坦福大学医学院K. Christopher Garcia课题组揭示，白介素-10（IL-10）的促炎和消炎功能是基于结构的解偶联。该项研究成果发表在2021年3月19日出版的《科学》杂志上。

他们通过基于电镜分辨率为3.5埃的方法确定IL-10受体（IL-10R）复合物的结构，采用基于结构的方法对IL-10的多效性进行反卷积。六聚体结构显示了IL-10和IL-10Rα如何形成复合表面以与共享的信号受体IL-10Rβ接合，从而实现了部分激动剂的设计。

具有一系列IL-10Rβ结合强度的IL-10变体揭示了整个免疫细胞群体在响应阈值上的实质性差异，从而提供了一种操纵IL-10细胞类型选择性的手段。一些变体通过抑制巨噬细胞激活，而不刺激炎症性CD8 + T细胞，从而解除了IL-10的主要相反功能，从而表现出了偏向骨髓的活性。这些结果提供了用于调节IL-10的多效作用的机制蓝图。

据悉，IL-10是一种具有抗炎和免疫刺激特性的免疫调节细胞因子，在疾病中经常失调。

附：英文原文

Title: Structure-based decoupling of the pro- and anti-inflammatory functions of interleukin-10

Author: Robert A. Saxton, Naotaka Tsutsumi, Leon L. Su, Gita C. Abhiraman, Kritika Mohan, Lukas T. Henneberg, Nanda G. Aduri, Cornelius Gati, K. Christopher Garcia

Issue&Volume: 2021/03/19

Abstract: Interleukin-10 (IL-10) is an immunoregulatory cytokine with both anti-inflammatory and immunostimulatory properties and is frequently dysregulated in disease. We used a structure-based approach to deconvolute IL-10 pleiotropy by determining the structure of the IL-10 receptor (IL-10R) complex by cryo–electron microscopy at a resolution of 3.5 angstroms. The hexameric structure shows how IL-10 and IL-10Rα form a composite surface to engage the shared signaling receptor IL-10Rβ, enabling the design of partial agonists. IL-10 variants with a range of IL-10Rβ binding strengths uncovered substantial differences in response thresholds across immune cell populations, providing a means of manipulating IL-10 cell type selectivity. Some variants displayed myeloid-biased activity by suppressing macrophage activation without stimulating inflammatory CD8+ T cells, thereby uncoupling the major opposing functions of IL-10. These results provide a mechanistic blueprint for tuning the pleiotropic actions of IL-10.

DOI: 10.1126/science.abc8433

Source: https://science.sciencemag.org/content/371/6535/eabc8433