FXR protects against neonatal sepsis via enhancing the immunosuppressive function of MDSCs

The presence of myeloid-derived suppressor cells (MDSCs) during the early postnatal period plays a protective role against neonatal inflammation. However, the mechanisms regulating neonatal MDSCs remain to be fully elucidated. In this study, we report that the bile acid receptor Farnesoid X receptor (FXR) acts as a pivotal positive regulator of neonatal MDSCs. Using FXR-deficient (FXR-/-) mice and FDA-approved FXR agonist obeticholic acid (OCA), we demonstrated that FXR deficiency impairs the immunosuppressive and antibacterial functions of neonatal MDSCs, thereby exacerbating the severity of neonatal sepsis. Adoptive transfer of MDSCs alleviates sepsis severity in FXR-/- neonatal pups. Mechanistic studies reveal that HIF1a, a well-established regulator of MDSCs, is a direct transcriptional target of FXR. Patients with neonatal sepsis displayed reduced MDSC frequencies and impaired expression of FXR and HIF-1a, which was negatively correlate with the clinical parameters. These observations highlight the important role of FXR in neonatal MDSCs and its therapeutic potential in neonatal sepsis. Overall design: PMN-MDSCs sorted from spleens of FXR-/- and WT neonatal mice (7 days). PMN-MDSCs were resuspended in TRIzol for RNA extraction. Library preparation was performed using a SMARTer Ultra low RNA kit, and sequencing was conducted on an Illumina NovaSeq platform (150-bp paried-end).

髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）在产后早期的存在对新生儿炎症具有保护作用。然而，调控新生儿MDSCs的具体机制仍有待完全阐明。本研究证实，胆汁酸受体法尼醇X受体（Farnesoid X receptor, FXR）是新生儿MDSCs的关键正向调控因子。本研究使用FXR敲除（FXR-/-）小鼠以及美国食品药品监督管理局（Food and Drug Administration, FDA）批准的FXR激动剂奥贝胆酸（obeticholic acid, OCA），结果表明FXR缺失会削弱新生儿MDSCs的免疫抑制与抗菌功能，进而加重新生儿脓毒症的病情严重程度。过继转移MDSCs可减轻FXR-/-新生幼鼠的脓毒症严重程度。机制研究显示，作为已被广泛证实的MDSCs调控因子的缺氧诱导因子1α（HIF1a），是FXR的直接转录靶标。新生儿脓毒症患者的MDSCs占比降低，且FXR与HIF-1α的表达受损，上述变化与临床参数呈负相关。上述发现凸显了FXR在新生儿MDSCs中的重要作用，以及其在新生儿脓毒症中的治疗潜力。
实验设计：从FXR-/-及野生型（wild type, WT）新生小鼠（出生7日龄）的脾脏中分选多形核髓系来源抑制细胞（PMN-MDSCs），将其重悬于TRIzol试剂中以提取RNA。文库构建采用SMARTer Ultra低起始量RNA建库试剂盒，测序在Illumina NovaSeq平台上完成，采用150 bp双端测序策略。