The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72. However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8^−/− mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8^−/− mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8^−/− macrophages. Smcr8^−/− mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand–receptor contact causes inflammatory disease in SMCR8-deficient mice.

SMCR8-WDR41-C9ORF72 复合物是自噬和溶酶体功能的调节剂。自身免疫和炎症性疾病归因于小鼠中Smcr8或C9orf72的功能丧失突变。据报道，在人类中，自身免疫先于由C9ORF72突变引起的肌萎缩侧索硬化。然而，由 C9ORF72 或 SMCR8 缺陷引起的自身免疫和炎症的细胞和分子机制仍然未知。在这里，我们表明在Smcr8 ^-/-小鼠中观察到的脾肿大、淋巴结肿大和活化的循环 T 细胞通过三重敲除内体 Toll 样受体 (TLR) TLR3、TLR7 和 TLR9 得以挽救。来自Smcr8的髓细胞^-/-小鼠产生过多的炎性细胞因子，以响应在生长培养基中施用的内吞 TLR3、TLR7 或 TLR9 配体，以及响应通过吞噬作用内化的 TLR2 或 TLR4 配体。这些缺陷可能源于由 LysoTracker 阳性囊泡的积累和延迟的吞噬体成熟引起的 TLR 信号延长，这两者都在Smcr8 ^-/-巨噬细胞中观察到。Smcr8 ^-/-小鼠还表现出对葡聚糖硫酸钠诱导的结肠炎的易感性升高，这与 TLR3、TLR7 或 TLR9 信号传导的增加无关。WDR41 的缺乏导致 SMCR8 的表型缺失。我们的研究结果提供了证据，表明长期配体 - 受体接触导致的过度内体 TLR 信号传导会导致 SMCR8 缺陷小鼠的炎症性疾病。