DataSheet_1_Loss of interleukin-1 beta is not protective in the lupus-prone NZM2328 mouse model.pdf

Aberrant activation of the innate immune system is a known driver of lupus pathogenesis. Inhibition of the inflammasome and its downstream signaling components in murine models of lupus has been shown to reduce the severity of disease. Interleukin-1 beta (IL-1β) is a proinflammatory cytokine released from cells following inflammasome activation. Here, we examine how loss of IL-1β affects disease severity in the lupus-prone NZM2328 mouse model. We observed a sex-biased increase in immune complex deposition in the kidneys of female mice in the absence of IL-1β that corresponds to worsened proteinuria. Loss of IL-1β did not result in changes in overall survival, anti-dsDNA autoantibody production, or renal immune cell infiltration. RNA-sequencing analysis identified upregulation of TNF and IL-17 signaling pathways specifically in females lacking IL-1β. Increases in these signaling pathways were also found in female patients with lupus nephritis, suggesting clinical relevance for upregulation of these pathways. Together, these data suggest that inhibition of the inflammasome or its downstream elements that block IL-1β signaling may need to be approached with caution in SLE, especially in patients with renal involvement to prevent potential disease exacerbation.

先天免疫系统的异常激活是狼疮发病机制已知的主要驱动力。在狼疮小鼠模型中，抑制炎性小体及其下游信号传导成分已被证明可以减轻疾病严重程度。在炎性小体激活后，细胞释放的IL-1β（白介素-1β）是一种促炎细胞因子。本研究旨在探讨IL-1β缺失如何影响狼疮易感NZM2328小鼠模型的疾病严重程度。我们观察到，在缺乏IL-1β的情况下，雌性小鼠肾脏中免疫复合物的沉积增加呈性别偏向性，这与加重蛋白尿相一致。IL-1β的缺失并未导致整体生存率、抗dsDNA自身抗体的产生或肾脏免疫细胞浸润的改变。RNA测序分析发现，TNF和IL-17信号通路在缺乏IL-1β的雌性小鼠中特异性上调。这些信号通路在狼疮性肾炎女性患者中的增加也得到证实，表明这些通路的上调具有临床相关性。综上所述，这些数据表明，抑制炎性小体或其下游阻断IL-1β信号传导的元素可能需要在系统性红斑狼疮（SLE）中谨慎对待，尤其是在肾脏受累的患者中，以防止潜在的疾病恶化。