Department of Molecular Mechanisms of Disease, University of Zurich, 8057 Zurich, Switzerland.
Molecular Life Science Ph.D. Program of the Life Science Zurich Graduate School, 8057 Zurich, Switzerland.
J Immunol. 2019 Mar 1;202(5):1406-1416. doi: 10.4049/jimmunol.1801107. Epub 2019 Jan 23.
Mice deficient for ADP-ribosyltransferase diphteria toxin-like 1 (ARTD1) are protected against microbially induced inflammation. To address the contribution of ARTD1 to inflammation specifically in myeloid cells, we generated an mouse strain with conditional ARTD1 deficiency in myeloid lineages and examined the strain in three disease models. We found that ARTD1, but not its enzymatic activity, enhanced the transcriptional activation of distinct LPS-induced genes that included IL-12, TNF-α, and IL-6 in primary bone marrow-derived macrophages and LPS-induced IL-12/18-IFN-γ signaling in mice. The loss of in myeloid cells also reduced the T1 response to and impaired immune control of the bacteria. Furthermore, mice failed to control tumor growth in a s.c. MC-38 model of colon cancer, which could be attributed to reduced T1 and CD8 responses. Together, these data provide strong evidence for a cell-intrinsic role of ARTD1 in myeloid cells that is independent of its enzymatic activity and promotes type I immunity by promoting IL-12/18 expression.
缺乏 ADP-ribosyltransferase 假单胞菌毒素样 1（ARTD1）的小鼠可免受微生物诱导的炎症。为了专门研究 ARTD1 在髓样细胞中炎症的贡献，我们生成了一种在髓样谱系中条件性缺乏 ARTD1 的 小鼠品系，并在三种疾病模型中对其进行了研究。我们发现，ARTD1（而非其酶活性）增强了特定 LPS 诱导基因的转录激活，包括原代骨髓来源的巨噬细胞中的 IL-12、TNF-α 和 IL-6，以及 小鼠中的 LPS 诱导的 IL-12/18-IFN-γ 信号。髓样细胞中 的缺失也降低了对 的 T1 反应，并损害了对细菌的免疫控制。此外， 小鼠在 MC-38 结直肠癌皮下模型中无法控制肿瘤生长，这可归因于 T1 和 CD8 反应的减少。总之，这些数据为 ARTD1 在髓样细胞中的细胞内在作用提供了强有力的证据，该作用独立于其酶活性，并通过促进 IL-12/18 表达来促进 I 型免疫。
