J Immunol：单核细胞在加剧败血症症状中发挥积极作用

    炎症反应是一种常见机制，是一把双刃剑，正确的炎症反应对于抵御感染入侵以及消除异常细胞是必要的。而另一方面，过度的炎症导致多种慢性疾病。患者感染败血症，他们经过初始强烈的炎症反应后，免疫系统会受到抑制，其中免疫细胞不再响应细菌产生的毒性分子。

    加拿大研究人员Biswas说：败血症的死亡率在世界各地重症监护病房中居高不下，但一直没有可靠的生物标志物或特定的药物来开展治疗。但Biswas和他的同事最近发现一个特定的细胞群体--单核细胞在加剧败血症症状中发挥积极作用。

    研究人员认为这些细胞在调节炎症和败血症的免疫功能中发挥重要作用。然而，患者体内存在各种单核细胞亚型，其中每一类亚型细胞表面表达的蛋白都不同，这就有可能激活不同的下游信号通路。在这项新研究中，Biswas和他的同事们专注于一种受体蛋白CD16，CD16主要表达在单核细胞亚型中。在脓毒症患者血液中，研究人员发现表达CD16的单核细胞数量明显增加。

    早期研究揭示败血症主要是Toll样受体4（TLR4）蛋白信号转导通路的激活。Biswas等同事了解到CD16的激活调节单核细胞中TLR4信号，促使败血症进一步发展。他们观察到单核细胞表达的CD16能导致炎症基因表达增加。然而，CD16介导的信号也导致炎症抑制信号转导途径分子的表达，但这些分子只在败血症初始炎症阶段发挥作用。虽然表达CD16的单核细胞似乎是败血症发展重要的促进因素，但Biswas指出研究结果需需要进一步证实，然后才考虑其研究成果能否用于治疗目的。

CD16 Regulates TRIF-Dependent TLR4 Response in Human Monocytes and Their Subsets

Irina N. Shalova*, Tasneem Kajiji*, Jyue Yuan Lim*, et al.

Blood monocytes recognize Gram-negative bacteria through the TLR4, which signal via MyD88- and TRIF-dependent pathway to trigger an immune-inflammatory response. However, a dysregulated inflammatory response by these cells often leads to severe pathologies such as sepsis. We investigated the role of CD16 in the regulation of human monocyte response to Gram-negative endotoxin and sepsis. Blood monocytes from sepsis patients demonstrated an upregulation of several TRIF-dependent genes as well as a selective expansion of CD16-expressing (CD16+) monocytes. Gene expression and biochemical studies revealed CD16 to regulate the TRIF-dependent TLR4 pathway in monocytes by activating Syk, IFN regulatory factor 3, and STAT1, which resulted in enhanced expression of IFNB, CCL5, and CXCL10. CD16 also upregulated the expression of IL-1R–associated kinase M and IL-1 receptor antagonist, which are negative regulators of the MyD88-dependent pathway. CD16 overexpression or small interfering RNA knockdown in monocytes confirmed the above findings. Interestingly, these results were mirrored in the CD16+ monocyte subset isolated from sepsis patients, providing an in vivo confirmation to our findings. Collectively, the results from the current study demonstrate CD16 as a key regulator of the TRIF-dependent TLR4 pathway in human monocytes and their CD16-expressing subset, with implications in sepsis.