Molecular Stethoscope Inc., 259 E Grand Avenue, South San Francisco, CA 94080, United States.
Department of Bioengineering and Department of Applied Physics, Stanford University and Chan Zuckerberg Biohub, Stanford, CA 94305, United States.
EBioMedicine. 2022 Sep;83:104242. doi: 10.1016/j.ebiom.2022.104242. Epub 2022 Aug 30.
Inflammatory and immune responses are essential and dynamic biological processes that protect the body against acute and chronic adverse stimuli. While conventional protein markers have been used to evaluate systemic inflammatory response, the immunological response to stimulation is complex and involves modulation of a large set of genes and interacting signalling pathways of innate and adaptive immune systems. There is a need for a non-invasive tool that can comprehensively evaluate and monitor molecular dysregulations associated with inflammatory and immune responses in circulation and in inaccessible solid organs.
Here we utilized cell-free messenger RNA (cf-mRNA) RNA-Seq whole transcriptome profiling and computational biology to temporally assess lipopolysaccharide (LPS) induced and JAK inhibitor modulated inflammatory and immune responses in mouse plasma samples.
Cf-mRNA profiling displayed a pattern of systemic immune responses elicited by LPS and dysregulation of associated pathways. Moreover, attenuation of several inflammatory pathways, including STAT and interferon pathways, were observed following the treatment of JAK inhibitor. We further identified the dysregulation of liver-specific transcripts in cf-mRNA which reflected changes in the gene-expression pattern in this generally inaccessible biological compartment.
Using a preclinical mouse model, we demonstrated the potential of plasma cf-mRNA profiling for systemic and organ-specific characterization of drug-induced molecular alterations that are associated with inflammatory and immune responses.
Molecular Stethoscope.
炎症和免疫反应是保护身体免受急性和慢性不良刺激的必要和动态的生物学过程。虽然传统的蛋白质标志物已被用于评估全身炎症反应，但对刺激的免疫反应是复杂的，涉及到固有和适应性免疫系统的大量基因和相互作用的信号通路的调节。需要一种非侵入性的工具，可以全面评估和监测与循环和难以接近的实体器官中的炎症和免疫反应相关的分子失调。
在这里，我们利用无细胞信使 RNA（cf-mRNA）RNA-Seq 全转录组谱分析和计算生物学，在小鼠血浆样本中，从时间上评估脂多糖（LPS）诱导和 JAK 抑制剂调节的炎症和免疫反应。
cf-mRNA 分析显示了 LPS 引发的全身免疫反应模式和相关途径的失调。此外，在 JAK 抑制剂治疗后，观察到几种炎症途径（包括 STAT 和干扰素途径）的减弱。我们进一步确定了 cf-mRNA 中肝脏特异性转录物的失调，这反映了这个通常难以进入的生物隔室中基因表达模式的变化。
使用临床前小鼠模型，我们证明了血浆 cf-mRNA 分析在与炎症和免疫反应相关的药物诱导的分子改变的全身和器官特异性特征化方面的潜力。
分子听诊器。
