Institute of Molecular Medicine, Feinstein Institutes for Medical Research , Manhasset, NY, USA.
Department of Molecular Medicine, Zucker School of Medicine at Hofstra-Northwell, Hempstead, NY, USA.
J Exp Med. 2023 Dec 4;220(12). doi: 10.1084/jem.20230018. Epub 2023 Oct 18.
Infection is able to promote innate immunity by enhancing a long-term myeloid output even after the inciting infectious agent has been cleared. However, the mechanisms underlying such a regulation are not fully understood. Using a mouse polymicrobial peritonitis (sepsis) model, we show that severe infection leads to increased, sustained myelopoiesis after the infection is resolved. In post-infection mice, the tissue inhibitor of metalloproteinases 1 (TIMP1) is constitutively upregulated. TIMP1 antagonizes the function of ADAM10, an essential cleavage enzyme for the activation of the Notch signaling pathway, which suppresses myelopoiesis. While TIMP1 is dispensable for myelopoiesis under the steady state, increased TIMP1 enhances myelopoiesis after infection. Thus, our data establish TIMP1 as a molecular reporter of past infection in the host, sustaining hyper myelopoiesis and serving as a potential therapeutic target for modulating HSPC cell fate.
感染能够通过增强长期髓系细胞生成来促进先天免疫，即使在引发感染的病原体已被清除后也是如此。然而，这种调节的机制尚不完全清楚。使用小鼠多微生物性腹膜炎（败血症）模型，我们发现严重感染导致感染解决后骨髓细胞生成增加且持续。在感染后小鼠中，组织金属蛋白酶抑制剂 1（TIMP1）持续上调。TIMP1 拮抗 ADAM10 的功能，ADAM10 是 Notch 信号通路激活的必需切割酶，该通路抑制骨髓细胞生成。虽然 TIMP1 在稳态下对骨髓细胞生成不是必需的，但增加的 TIMP1 增强了感染后的骨髓细胞生成。因此，我们的数据将 TIMP1 确立为宿主过去感染的分子报告物，维持过度的骨髓细胞生成，并作为调节 HSPC 细胞命运的潜在治疗靶标。
