探讨免疫应答的消退机制对促进持续性炎症及时消退、抑制免疫系统过度反应从而干预相关疾病的发生发展具有重要意义。我们前期研究发现消退相关分子模式糖调节蛋白78(Grp78)能结合模式识别受体CD14，但与CD14结合传统配体LPS不同，CD14结合Grp78后诱导TLR4非炎症性内吞、抑制其信号分子激活，提示Grp78参与诱导免疫炎症消退，但作用机理尚不清楚。由此推测，Grp78能否通过结合CD14干预其TLR4依赖性及非依赖性的信号转导，参与诱导炎症消退、维持免疫自稳？据此，本项目拟研究结合Grp78/LPS对CD14和TLR4的功能、信号通路激活和细胞命运的影响及差异，明确Grp78通过CD14参与诱导免疫炎症消退的功能及机制；同时，明确CD14通过结合不同配体调节TLR4介导的炎症过程的关键分子，探寻CD14在不同的环境中如何调控天然免疫反应的平衡与稳定，为相关疾病靶标药物设计提供新思路

Immunological responses can be distilled into four fundamental, interdependent processes: recognition, response, regulation and resolution. Appropriate immunological recognition is of the utmost importance. However, of equal importance is the regulation and, thereafter, resolution of the acute inflammatory response. Failure of the latter is an important component of chronic inflammatory diseases, autoimmune disease, obesity, and wound repairing. A wide range of soluble molecules contribute to the regulation and resolution of inflammation. Evidence has emerged that resolution-associated molecular patterns (RAMPs) which are defined as highly evolutionarily conserved, multi-functional, constitutively expressed proteins, exert immunoregulatory activity dependent upon their rapid decompartmentalization from the intracellular environment either actively, following cell stress, or passively via necrotic cell death. Our previous report showed that Grp78 could increase the frequency of regulatory B cells which produced IL-10 and highly expressed PD-L1 and FasL, resulting in suppression of T cell proliferation and induce myeloid antigen presenting cells to maintained tolerogenic signature upon LPS stimulation. For its potent immunomodulatory properties, Grp78 has been defined as one of RAMPs. However, it is not clear how Grp78 feeds regulatory and anti-inflammatory signals into immunological networks to help restore immunological homeostasis. In our study, we found that Grp78 colocalized with CD14 at plasma membrane to enhance TLR4 endocytosis. However, unfamiliar with TLR4 endocytosis mediated by LPS binding with CD14 which triggers TRIF signal transduction, this Grp78 mediated TLR4 endocytosis fails to activate TRIF signal. To elucidate how Grp78 participates in immune resolution through engagement with CD14, changes of function and activation of signal transduction mediated by CD14 and TLR4 would be investigated. Furthermore, disparities in this changes between Grp78 and LPS engagement with CD14 would be analyzed to uncover how CD14 can influence the sensitivity and the quality of the innate immune response. This study will guide future studies to treat immune resolution related disease.