The PIK3C3/VPS34 subunit of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex plays a role in both canonical and noncanonical autophagy, key processes that control immune-cell responsiveness to a variety of stimuli. Our previous studies found that PIK3C3 is a critical regulator that controls the development, homeostasis, and function of dendritic and T cells. In this study, we investigated the role of PIK3C3 in myeloid cell biology using myeloid cell-specific Pik3c3-deficient mice. We found that Pik3c3-deficient macrophages express increased surface levels of major histocompatibility complex (MHC) class I and class II molecules. In addition, myeloid cell-specific Pik3c3 ablation in mice caused a partial impairment in the homeostatic maintenance of macrophages expressing the apoptotic cell uptake receptor TIM-4. Pik3c3 deficiency caused phenotypic changes in myeloid cells that were dependent on the early machinery (initiation/nucleation) of the classical autophagy pathway. Consequently, myeloid cell-specific Pik3c3-deficient animals showed significantly reduced severity of experimental autoimmune encephalomyelitis (EAE), a primarily CD4⁺ T-cell-mediated mouse model of multiple sclerosis (MS). This disease protection was associated with reduced accumulation of myelin-specific CD4⁺ T cells in the central nervous system and decreased myeloid cell IL-1β production. Further, administration of SAR405, a selective PIK3C3 inhibitor, delayed disease progression. Collectively, our studies establish PIK3C3 as an important regulator of macrophage functions and myeloid cell-mediated regulation of EAE. Our findings also have important implications for the development of small-molecule inhibitors of PIK3C3 as therapeutic modulators of MS and other autoimmune diseases.

III 类磷脂酰肌醇 3 激酶 (PtdIns3K) 复合物的 PIK3C3/VPS34 亚基在经典和非经典自噬中发挥作用，这是控制免疫细胞对各种刺激的反应的关键过程。我们之前的研究发现，PIK3C3 是控制树突状细胞和 T 细胞发育、稳态和功能的关键调节因子。在这项研究中，我们使用骨髓细胞特异性Pik3c3缺陷小鼠研究了 PIK3C3 在骨髓细胞生物学中的作用。我们发现Pik3c3缺陷的巨噬细胞表达主要组织相容性复合物 (MHC) I 类和 II 类分子的表面水平增加。此外，小鼠中骨髓细胞特异性的Pik3c3消融导致表达凋亡细胞摄取受体 TIM-4 的巨噬细胞的稳态维持部分受损。 Pik3c3缺陷导致骨髓细胞表型变化，这些变化依赖于经典自噬途径的早期机制（起始/成核）。因此，骨髓细胞特异性Pik3c3缺陷动物的实验性自身免疫性脑脊髓炎 (EAE) 的严重程度显着降低，EAE 是一种主要由 CD4 ⁺ T 细胞介导的多发性硬化症 (MS) 小鼠模型。这种疾病保护作用与中枢神经系统中髓磷脂特异性 CD4 ⁺ T 细胞积累的减少以及髓样细胞 IL-1β 产生的减少有关。此外，给予 SAR405（一种选择性 PIK3C3 抑制剂）可延缓疾病进展。总的来说，我们的研究确定 PIK3C3 是巨噬细胞功能和骨髓细胞介导的 EAE 调节的重要调节因子。 我们的研究结果对于开发 PIK3C3 小分子抑制剂作为 MS 和其他自身免疫性疾病的治疗调节剂也具有重要意义。