The initiation and progression of autoimmune disorders such as multiple sclerosis (MS) is linked to aberrant cholesterol metabolism and overt inflammation. Liver X receptors (LXR) are nuclear receptors that function at the crossroads of cholesterol metabolism and immunity, and their activation is considered a promising therapeutic strategy to attenuate autoimmunity. However, despite clear functional heterogeneity and cell-specific expression profiles, the impact of the individual LXR isoforms on autoimmunity remains poorly understood. Here, we show that LXRα and LXRβ have an opposite impact on immune cell function and disease severity in the experimental autoimmune encephalomyelitis model, an experimental MS model. While Lxrα deficiency aggravated disease pathology and severity, absence of Lxrβ was protective. Guided by flow cytometry and by using cell-specific knockout models, reduced disease severity in Lxrβ-deficient mice was primarily attributed to changes in peripheral T cell physiology and occurred independent from alterations in microglia function. Collectively, our findings indicate that LXR isoforms play functionally non-redundant roles in autoimmunity, potentially having broad implications for the development of LXR-based therapeutic strategies aimed at dampening autoimmunity and neuroinflammation.

自身免疫性疾病如多发性硬化症 (MS) 的发生和进展与胆固醇代谢异常和明显炎症有关。肝 X 受体 (LXR) 是在胆固醇代谢和免疫的十字路口起作用的核受体，它们的激活被认为是减弱自身免疫的有希望的治疗策略。然而，尽管有明显的功能异质性和细胞特异性表达谱，单个 LXR 同种型对自身免疫的影响仍然知之甚少。在这里，我们表明 LXRα 和 LXRβ 在实验性自身免疫性脑脊髓炎模型（一种实验性 MS 模型）中对免疫细胞功能和疾病严重程度具有相反的影响。虽然Lxrα缺乏会加重疾病的病理和严重程度，但Lxrβ的缺乏是保护性的。在流式细胞仪和使用细胞特异性敲除模型的指导下，Lxrβ 缺陷小鼠的疾病严重程度降低主要归因于外周 T 细胞生理学的变化，并且与小胶质细胞功能的改变无关。总的来说，我们的研究结果表明 LXR 同种型在自身免疫中发挥功能非冗余作用，可能对开发基于 LXR 的旨在抑制自身免疫和神经炎症的治疗策略具有广泛的影响。