NLRP3炎性小体异常活化可引发多种炎症疾病，但激活NLRP3的机制尚未明确。前期我们发现巨噬细胞表达MS4A6D可促进[Ca2+]内流并诱导NLRP3炎性小体活化，但其如何调节[Ca2+]内流尚未知。本课题拟：1）使用膜片钳技术探讨MS4A6D有钙库操纵的钙离子(SOC)通道功能并诱导[Ca2+]ex内流；2）使用点突变、截短表达及CO-IP等技术，证明MS4A6D能与Syk激酶结合，激活下游PLCr-IP3-IP3R通路诱导内质网[Ca2+]i释放；3）使用Ms4a6d-/-小鼠，建立[Ca2+]依赖性λ-卡拉胶诱导的足垫肿胀及DSS诱导的结肠炎模型，明确MS4A6D促进[Ca2+]依赖性NLRP3活化及其机制；4）使用油酸/a-亚麻酸配体处理，探讨操纵MS4A6D信号对λ-卡拉胶诱导的足垫肿胀炎症的调节作用。本研究将为NLRP3介导的炎性疾病提供新干预措施。

Hyperactivation of NLRP3- inflammasome contributes to the pathogenesis of multiple diseases whereas the mechanisms underlying control the activation of NLRP3- inflammasome remain poorly understood. Our previous work have demonstrated that macrophages-derived MS4A6D promotes [Ca2+] flux in macrophages, by thus enhances NLRP3 activation and induces the release of IL-1β and IL-18 upon macrophages were treated by NLRP3- inflammasome stimuli. Nevertheless, how MS4A6D induces [Ca2+] influx is unclear. Here we would try to do the following experiments: 1) Investigate whether MS4A6D is function as a voltage-gated Ca2+ channel (VOC) or a receptor-operated calcium channel (ROC) with using the patch clamp technique, by thus it induce excellular [Ca2+] influx; 2) Demonstrate MS4A6D promotes the release of [Ca2+] from (endoplasmic reticulum, ER) via interacting with Syk kinase, thereafter, activating Syk-PLCr-IP3-IP3R cascades to induce [Ca2+] release from ER; 3) Using the Ms4a6d-/- mice to establish NLRP3-dependent mouse models including carrageenan-induced footpad swelling and Dextran Sodium Sulfate (DSS)-induced Colitis, finally demonstrate that MS4A6D can promote [Ca2+]-dependent NLRP3-inflammasome activation in vivo; 4) Illustrate that MS4A6D can control the pathogenesis of carrageenan-induced footpad swelling and DSS-induced Colitis through treating the WT mice with the MS4A6D agonist antibodies or its ligands including oleic acid/alpha-linolenic acid. These findings would highlight MS4A6D as a prospective target for treating NLRP3- associated inflammatory disorders.