YTHDF2介导IL-6R mRNA m6A修饰在抑制脓毒症炎症反应中的作用及机制

脓毒症是严重烧伤的常见并发症，其本质是机体过度释放炎症介质引起的炎性反应失控，已成为导致临床烧伤患者死亡的重要原因之一。因此，阐明调控脓毒症炎症反应的分子机制具有重要意义。我们前期首次发现，YTHDF2作为m6A甲基化的特异性“阅读器”，可抑制促发脓毒症的关键炎症介质HMGB1的胞外释放，进而对YTHDF2介导m6A修饰在抑制脓毒症炎症反应中的作用及机制进行了初探，基于所获创新发现并结合有关文献，提出如下假设：YTHDF2可能通过直接结合IL-6R mRNA 3ʹ-UTR 的m6A修饰位点，促进IL-6R mRNA的降解，从而下调IL-6R的表达，进而抑制炎症通路JAK2/STAT1的活化，最终通过抑制HMGB1的乙酰化而抑制HMGB1的胞外释放，发挥抗炎效应。本研究将证实上述假设通路是m6A修饰调节脓毒症炎症反应的新机制，以期为探索以该通路为靶标的抗脓毒症新措施提供科学依据。

Sepsis, a common complication of severe burns characterized by uncontrolled inflammatory response resulting from excessive release of inflammatory mediators, has become the leading cause of death in clinical burn patients. Therefore, it is of great significance to elucidate the molecular mechanisms regarding inflammatory response regulation of sepsis. Our preliminary data for the first time showed that YTHDF2 (a specific "reader" for m6A methylation) can inhibit the extracellular release of HMGB1, which is the key inflammatory mediator of sepsis. Furthermore, we preliminarily explored the mechanism of YTHDF2-mediated m6A modification in inhibiting the inflammatory response of sepsis, and obtained innovative findings. Based on our preliminary discoveries, we hypothesize that YTHDF2 may directly bind to the m6A modification site in IL-6R mRNA 3ʹ-UTR, leading to the enhancement of IL-6R mRNA degradation and the subsequent inhibition of IL-6R expression, which further suppresses the activation of inflammatory pathway JAK2/STAT1, thus, the extracellular release of HMGB1 is repressed by inhibiting its acetylation, and finally the anti-inflammatory effect is displayed by above pathway. In the present project, we will reveal that the hypothesized pathway is a novel mechanism by which m6A modification regulates the inflammatory response in sepsis, which may provide scientific evidences for exploring promising anti-sepsis strategies targeted the corresponding pathway.