Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Function (Oxf). 2024 Jul 11;5(4). doi: 10.1093/function/zqae015.
Pancreatic β-cells are essential for survival, being the only cell type capable of insulin secretion. While they are believed to be vulnerable to damage by inflammatory cytokines such as interleukin-1 beta (IL-1β) and interferon-gamma, we have recently identified physiological roles for cytokine signaling in rodent β-cells that include the stimulation of antiviral and antimicrobial gene expression and the inhibition of viral replication. In this study, we examine cytokine-stimulated changes in gene expression in human islets using single-cell RNA sequencing. Surprisingly, the global responses of human islets to cytokine exposure were remarkably blunted compared to our previous observations in the mouse. The small population of human islet cells that were cytokine responsive exhibited increased expression of IL-1β-stimulated antiviral guanylate-binding proteins, just like in the mouse. Most human islet cells were not responsive to cytokines, and this lack of responsiveness was associated with high expression of genes encoding ribosomal proteins. We further correlated the expression levels of RPL5 with stress response genes, and when expressed at high levels, RPL5 is predictive of failure to respond to cytokines in all endocrine cells. We postulate that donor causes of death and isolation methodologies may contribute to stress of the islet preparation. Our findings indicate that activation of stress responses in human islets limits cytokine-stimulated gene expression, and we urge caution in the evaluation of studies that have examined cytokine-stimulated gene expression in human islets without evaluation of stress-related gene expression.
胰岛β细胞对于生存至关重要，是唯一能够分泌胰岛素的细胞类型。虽然人们认为它们容易受到白细胞介素-1β (IL-1β) 和干扰素-γ等炎症细胞因子的损伤，但我们最近在啮齿动物β细胞中发现了细胞因子信号的生理作用，包括刺激抗病毒和抗菌基因表达以及抑制病毒复制。在这项研究中，我们使用单细胞 RNA 测序检查了人胰岛中细胞因子刺激引起的基因表达变化。令人惊讶的是，与我们之前在小鼠中观察到的情况相比，细胞因子暴露后人类胰岛的整体反应明显减弱。对细胞因子有反应的人类胰岛细胞的小群体表现出 IL-1β 刺激的抗病毒鸟苷酸结合蛋白表达增加，就像在小鼠中一样。大多数人类胰岛细胞对细胞因子没有反应，这种无反应性与编码核糖体蛋白的基因的高表达有关。我们进一步将 RPL5 的表达水平与应激反应基因相关联，并且当以高水平表达时，RPL5 可以预测所有内分泌细胞对细胞因子的反应失败。我们推测供体死亡原因和分离方法可能导致胰岛制备的应激。我们的研究结果表明，人胰岛中应激反应的激活限制了细胞因子刺激的基因表达，因此我们强烈建议在评估未经应激相关基因表达评估而检查人胰岛中细胞因子刺激基因表达的研究时要谨慎。
