减少肺部感染炎症反应的新靶点：TREM-1
急性呼吸道感染造成每年4百万以上的死亡，中性粒细胞在肺部感染的固有免疫应答中发挥重要作用。中性粒细胞通过模式识别和分泌抗菌物质识别和消灭感染部位的病原体。除了消灭感染病原体，中性粒细胞也能驱动炎症反应，从而导致肺功能损伤甚至严重的并发症。
有研究表明中性粒细胞炎性蛋白——髓系细胞触发受体1（TREM-1，triggering receptor expressed on myeloid cells）能扩大炎症反应，因此有人推测敲除TREM-1后能减少炎症反应，提高感染存活率。然而在研究过程中，研究人员却发现了相反的结果，敲除TREM-1显著增加绿脓杆菌感染的小鼠死亡率，爱荷华大学茱莉亚-泰特的研究团队在12月17日的《临床研究杂志》发表了相关结果。
中性粒细胞敲除TREM-1/3不影响细胞的杀菌活性，吞噬能力和趋化作用，然而TREM-1/3敲除小鼠肺部免疫组化显示迁移到气道的中性粒细胞显著减少。深入研究表明虽然敲除TREM-1/3的中性粒细胞能穿过单层内皮细胞，但却不能穿过气道上皮细胞，因此不能有效地迁移到感染部位。
研究指出炎性蛋白TREM-1在中性粒细胞迁移中产生的作用出乎意料，针对TREM-1为靶点的治疗可能产生非预期的效果。此外，对TREM-1/3上皮迁移的进一步研究可能帮助找到调节中性粒细胞浸润的治疗靶点，通过控制迁移过程而不是经典的细胞因子信号来控制局部炎症反应。
Transepithelial migration of neutrophils into the lung requires TREM-1.
Klesney-Tait J, Keck K, Li X, Gilfillan S, Otero K, Baruah S, Meyerholz DK, Varga SM, Knudson CJ, Moninger TO, Moreland J, Zabner J, Colonna M.
J Clin Invest. 2013 Jan 2;123(1):138-49. doi: 10.1172/JCI64181. Epub 2012 Dec 17.
Abstract
Acute respiratory infections are responsible for more than 4 million deaths each year. Neutrophils play an essential role in the innate immune response to lung infection. These cells have an armamentarium of pattern recognition molecules and antimicrobial agents that identify and eliminate pathogens. In the setting of infection, neutrophil triggering receptor expressed on myeloid cells 1 (TREM-1) amplifies inflammatory signaling. Here we demonstrate for the first time that TREM-1 also plays an important role in transepithelial migration of neutrophils into the airspace. We developed a TREM-1/3-deficient mouse model of pneumonia and found that absence of TREM-1/3 markedly increased mortality following Pseudomonas aeruginosa challenge. Unexpectedly, TREM-1/3 deficiency resulted in increased local and systemic cytokine production. TREM-1/3-deficient neutrophils demonstrated intact bacterial killing, phagocytosis, and chemotaxis; however, histologic examination of TREM-1/3-deficient lungs revealed decreased neutrophil infiltration of the airways. TREM-1/3-deficient neutrophils effectively migrated across primary endothelial cell monolayers but failed to migrate across primary airway epithelia grown at the air-liquid interface. These data define a new function for TREM-1 in neutrophil migration across airway epithelial cells and suggest that it amplifies inflammation through targeted neutrophil migration into the lung.
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