SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress
SLC15A4 mediates M1-prone metabolic shifts in macrophages and guards immune cells from metabolic stress
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DOI：
10.1073/pnas.2100295118
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发表时间：
2021-08-17
影响因子：
11.1
通讯作者：
Toyama-Sorimachi, Noriko
中科院分区：
文献类型：
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作者：
Kobayashi, Toshihiko;Nguyen-Tien, Dat;Toyama-Sorimachi, Noriko
氨基酸和寡肽转运蛋白溶质载体家族15成员A4（SLC 15 A4）存在于溶酶体中并优先在免疫细胞中表达，在小鼠模型中狼疮和结肠炎的发病机制中起关键作用。Toll样受体（TLR）7/9和含核苷酸结合寡聚化结构域的蛋白1（NOD 1）介导的炎症反应需要SLC 15 A4功能，分别用于调节雷帕霉素复合物1（mTORC 1）的机制靶点或转运L-Ala-γ-D-Glu-内消旋-二氨基庚二酸，IL-12：白细胞介素-12（Tri-DAP）。在这里，我们进一步研究了SLC 15 A4如何指导炎症反应的机制。邻近依赖性生物素鉴定揭示糖酵解作为高度富集的基因本体论术语。在巨噬细胞中的通量体分析表明，SLC 15 A4损失导致丙酮酸到三羧酸循环的生物转化不足，同时增加对循环的氨解。此外，SLC 15 A4是TLR 9刺激后M1倾向性代谢变化和炎性IL-12细胞因子产生所必需的。SLC 15 A4可能与AMP激活的蛋白激酶（AMPK）和mTOR非常接近，并且SLC 15 A4缺陷损害TLR介导的AMPK激活。有趣的是，SLC 15 A4-完整但非SLC 15 A4-缺陷的巨噬细胞通过限制谷氨酰胺源的使用而变得对环境营养水平的波动具有抗性;因此，SLC 15 A4对于巨噬细胞的呼吸稳态是至关重要的。我们的研究结果揭示了一种代谢调节机制，其中氨基酸转运蛋白作为看门人，通过减轻代谢应激来保护免疫细胞在炎症组织中获得M1倾向代谢表型的能力。
The amino acid and oligopeptide transporter Solute carrier family 15 member A4 (SLC15A4), which resides in lysosomes and is preferentially expressed in immune cells, plays critical roles in the pathogenesis of lupus and colitis in murine models. Toll-like receptor (TLR) 7/9-and nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-mediated inflammatory responses require SLC15A4 function for regulating the mechanistic target of rapamycin complex 1 (mTORC1) or transporting L-Ala-gamma-D-Glu-meso-diaminopimelic acid, IL-12: interleukin-12 (Tri-DAP), respectively. Here, we further investigated the mechanism of how SLC15A4 directs inflammatory responses. Proximity-dependent biotin identification revealed glycolysis as highly enriched gene ontology terms. Fluxome analyses in macrophages indicated that SLC15A4 loss causes insufficient biotransformation of pyruvate to the tricarboxylic acid cycle, while increasing glutaminolysis to the cycle. Furthermore, SLC15A4 was required for M1-prone metabolic change and inflammatory IL-12 cytokine productions after TLR9 stimulation. SLC15A4 could be in close proximity to AMP-activated protein kinase (AMPK) and mTOR, and SLC15A4 deficiency impaired TLR-mediated AMPK activation. Interestingly, SLC15A4-intact but not SLC15A4-deficient macrophages became resistant to fluctuations in environmental nutrient levels by limiting the use of the glutamine source; thus, SLC15A4 was critical for macrophage's respiratory homeostasis. Our findings reveal a mechanism of metabolic regulation in which an amino acid transporter acts as a gatekeeper that protects immune cells' ability to acquire an M1-prone metabolic phenotype in inflammatory tissues by mitigating metabolic stress.