Table_2_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已知触发狼疮发病机制的因素。在狼疮小鼠模型中，通过抑制炎性小体及其下游信号传导成分，已被证实可以减轻疾病的严重程度。IL-1β（白介素-1β）是一种在炎性小体激活后由细胞释放的前炎症细胞因子。在本研究中，我们探讨了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呈性别偏向性增加，这与加重蛋白尿相一致。IL-1β的缺失并未导致总体生存率、抗dsDNA自身抗体的产生或肾脏免疫细胞浸润的改变。RNA测序分析识别出，在缺乏IL-1β的雌性小鼠中，TNF和IL-17信号通路被特异性上调。这些信号通路的增加也发现在狼疮性肾炎的雌性患者中，这表明这些通路的上调在临床上具有相关性。综合这些数据，表明抑制炎性小体或其下游元素，以阻断IL-1β信号传导的抑制策略，在系统性红斑狼疮（SLE）的治疗中可能需要谨慎对待，特别是在有肾脏侵犯的患者中，以防止潜在疾病的恶化。