钙敏感受体介导巨噬细胞NLRP3炎症小体的选择性激活在高血压发病中作用和机制研究

炎症小体是先天免疫反应的关键参与者，作为G蛋白偶联受体钙敏感受体（CaSR）可经Gαq/PLC/IP3/Ca2+↑或Gαi/AC/cAMP/PKA↓促进或抑制NLRP3炎症小体激活，但是否参与高血压发病尚不清楚。我们前期和预实验研究发现：随血压↑，CaSR表达↓，cAMP↑，“经典激活”促炎性M1型巨噬细胞（M1MΦ）增多，“替代激活”抗炎性M2MΦ减少，伴随NLRP3炎症小体激活。我们推测：高血压时，由于CaSR↓，在减少的M2MΦ中经Gαq抑制NLRP3炎症小体激活作用减弱；占优势的M1MΦ中经Gαi引发NLRP3炎症小体激活作用增强，促进血管和心肌重塑及高血压发生发展，为证实此假说，本项目拟从整体、细胞和分子水平探讨CaSR介导巨噬细胞NLRP3炎症小体选择性激活（不同表型MΦ经不同信号通路）作用和信号转导机制及对血压、血管和心肌重塑的影响和作用机制，为临床高血压防治提供新思路。

Inflammasomes are key participants in innate immune response.Calcium-sensing receptor (CaSR), a G protein-coupled receptor,can promote or inhibit the activation of nucleotide-binding and oligomerization domain (NOD)- like receptors family,pyrin domain containing 3(NLRP3) inflammasomes through Gαq/phospholipase C (PLC)/inositol 1,4,5-trisphosphate, (IP3)/Ca2+ pathway activation or Gαi/adenylate cyclase (AC)/ cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA) pathway inhibition, respectively.However, it is not clear whether it is involved in the pathogenesis of essential hypertension(EH). Our previous and preliminary studies found that with the increase of blood pressure, the expression of CaSR decreased, the content of cAMP increased, the number of “classically activated” proinflammatory M1 macrophages (M1MΦ) increased. Contrary, the number of “alternatively activated” anti-inflammatory M2MΦ decreased, accompanied by the activation of NLRP3 inflammasomes. Therefore, we hypothesized that in spontaneous hypertensive rats (SHR),the decrease of CaSR expression in reduced M2MΦ resulting in the decrease of intracellular calcium concentration mediated by Gαq/PLC/IP3 pathway attenuated the inhibition of NLRP3 inflammasomes activation.Whereas in the dominant M1MΦ, the decrease of CaSR expression attenuated the inhibition of AC via Gαi pathway, increased cAMP-PKA, enhanced the activation of NLRP3 inflammasomes, which promotes vascular and myocardial remodeling and EH development. To confirm this hypothesis, based on vivo, tissue, cell and molecular levels, we intend to explore the role of CaSR-mediated NLRP3 inflammasomes selective activation in macrophages (different phenotype MΦ via different signaling pathways) and the mechanism of signal transduction, as well as their effects and mechanisms on blood pressure, vascular and myocardial remodeling. Eventually, we provide new ideas and targets for clinical prevention and treatment of hypertension.