SLAMF7 Regulates Inflammatory Response In Macrophage During Polymicrobial Sepsis
作者单位：Center for Infection and Immunity and Guangdong Provincial Key Laboratory of Biomedical Imaging the Fifth Affiliated Hospital of Sun Yat-sen University National Clinical Research Center for Infectious Disease Shenzhen Third People's Hospital Guangzhou Women and Children's Medical Center Guangzhou Institute of Pediatrics Guangzhou Medical University The Sixth Affiliated Hospital of Guangzhou Medical University Qingyuan People's Hospital
会议名称：《第十四届全国免疫学学术大会》
会议日期：2021年
学科分类：1001[医学-基础医学(可授医学、理学学位)] 100104[医学-病理学与病理生理学] 10[医学]
关 键 词：Sepsis SLAMF7 Inflammatory cytokines SHIP1 TRAF6
摘 要：Uncontrolled microbe-triggered inflammation Results in multiple organ injury and shock in sepsis. However, the regulatory mechanisms that restrict cytokine storm are still elusive. Using gene screening, we identified an immunoglobulin-like receptor called Signaling Lymphocyte Activation Molecular Family-7(SLAMF7), as a key regulator of inflammation during sepsis. We found that the expression of SLAMF7 on monocytes and macrophages was significantly elevated in sepsis subjects and septic mice. SLAMF7 attenuated TLR dependent MAPKs and NF-κB signaling activation by co-operating with Src homology 2-containing inositol-5’-phosphatase1(SHIP1). Furthermore, SLAMF7 interacted with SHIP1 and TNF receptor associated factor 6(TRAF6) to inhibited K63 ubiquitination of TRAF6. In addition, we found that intracellular domain tyrosine phosphorylation sites of SLAMF7 and phosphatase domain of SHIP1 were indispensable for the interaction of SLAMF7/SHIP1/TRAF6 and the modulation of cytokines production. Finally, recombinant murine SLAMF7 peptide agonist or genetic knockout of SLAMF7 in mice demonstrated that SLAMF7 conferred protection against lethal sepsis and endotoxemia by suppressing inflammatory cytokines. Taken together, our findings reveal a critical negative regulatory role of SLAMF7 on cytokine storm in macrophages during polymicrobial sepsis, and therefore provide new sights into a novel diagnostic marker and therapeutic target for sepsis.