d-serine is synthesized by serine racemase (SR), a fold type II class of pyridoxal-5'-phosphate (PLP)-dependent enzyme. Whereas X-ray crystallography reveals that SR can be monomeric, reversible dimers having the highest racemase activity, or stable SR dimers resistant to both denaturation and reductive treatment, showing reduced racemase activity have been detected in microglia and astrocytes; the latter especially in oxidative or inflammatory environments. The microglial inflammatory environment depends largely on the TGFβ1-mediated regulation of inflammatory cytokines such as TNFα and IL1β. Here we evaluated the participation of TGFβ1 in the regulation of SR, and whether that regulation is associated with the induction of stable SR dimers in the microglia from adult mice. In contrast to the effect of lipopolysaccharide (LPS), TGFβ1 increased the formation of stable SR dimers and reduced the detection of monomers in microglia in culture. LPS or TGFβ1 did not change the amount of total SR. The increase of stable SR dimer was abolished when TGFβ1 treatment was done in the presence of the Smad inhibitor SIS3, showing that Smad3 has a role in the induction of stable dimers. Treatment with TGFβ1 + SIS3 also reduced total SR, indicating that the canonical TGFβ1 pathway participates in the regulation of the synthesis or degradation of SR. In addition, the decrease of IL1β, but not the decrease of TNFα induced by TGFβ1, was mediated by Smad3. Our results reveal a mechanism for the regulation of d-serine through the induction of stable SR dimers mediated by TGFβ1-Smad3 signaling in microglia.

中文翻译：

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TGFβ1-Smad3信号介导小胶质细胞中稳定的丝氨酸消旋酶二聚体的形成。

d-丝氨酸是由丝氨酸消旋酶（SR）合成的，它是II型折叠的吡ido醛5'-磷酸（PLP）依赖性酶。X射线晶体学表明SR可以是具有最高消旋酶活性的单体可逆二聚体，也可以是对变性和还原处理均具有抗性的稳定SR二聚体，表明在小胶质细胞和星形胶质细胞中检测到消旋消融酶活性降低；后者尤其是在氧化或炎性环境中。小胶质细胞炎性环境主要取决于TGFβ1介导的炎性细胞因子（如TNFα和IL1β）的调节。在这里，我们评估了TGFβ1在SR调控中的参与，以及该调控是否与成年小鼠小胶质细胞中稳定SR二聚体的诱导有关。与脂多糖（LPS）的作用相反，TGFβ1增加了稳定的SR二聚体的形成，并减少了培养物中小胶质细胞中单体的检测。LPS或TGFβ1不会改变总SR的量。当在Smad抑制剂SIS3存在下进行TGFβ1处理时，稳定的SR二聚体的增加被消除，这表明Smad3在诱导稳定的二聚体中起作用。用TGFβ1+ SIS3处理也降低了总SR，表明典型的TGFβ1途径参与了SR合成或降解的调节。另外，由Smad3介导IL1β的降低，但不是由TGFβ1诱导的TNFα的降低。我们的结果揭示了通过诱导小胶质细胞中TGFβ1-Smad3信号介导的稳定SR二聚体来调节d-丝氨酸的机制。