Abstract：
Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.
摘要：
专门的促溶解介质（SPM）可促进局部巨噬细胞的红细胞增多，但炎症早期的过量白细胞需要额外的白细胞清除机制才能消退。这里,在小鼠背侧气囊中研究了局部急性炎症的中性粒细胞清除机制。15-HEPE(15-羟基-5Z,8Z,11Z,13E,渗出物中的17Z-二十碳五烯酸）水平增加。活化的人中性粒细胞将15-HEPE转化为脂氧素A5(5S，6R,15S-三羟基-7E,9E,11Z,13E,17Z-二十碳五烯酸)，15-表脂氧素A5(5S,6R,15R-三羟基-7E,9E,11Z,13E,17Z-二十碳五烯酸)，和分辨率E4(RvE4;5S，15S-二羟基-6E,8Z,11Z,13E,17Z-二十碳五烯酸）。外源性15-epi-脂氧素A5，15-epi-脂氧素A4和结构脂氧素模拟物显着减少渗出物中性粒细胞并增加局部组织巨噬细胞的红细胞增多，与萘普生相比。15-表-脂氧素A5也清除渗出物中性粒细胞比刺激的巨噬细胞红细胞增多的表观局部能力更快，因此，用CD45.1变异中性粒细胞追踪渗出液中性粒细胞的命运。15-epi-lipoxinA5增强了过继转移的嗜中性粒细胞从袋渗出液到脾脏的退出，并显着增加脾SIRPa和MARCO巨噬细胞的吞噬。一起,这些发现证明了局部组织炎症中15-表脂氧素A5和RvE4的新的系统解决机制，它在远端与脾脏接触以激活巨噬细胞的红细胞增多作用，以清除组织渗出物中性粒细胞。
