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‐5 Z ,8 Z ,11 Z ,13 E ,17 Z ‐eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15‐HEPE to lipoxin A 5 (5 S ,6 R ,15 S ‐trihydroxy‐7 E ,9 E ,11 Z ,13 E ,17 Z ‐eicosapentaenoic acid), 15‐epi‐lipoxin A 5 (5 S ,6 R ,15 R ‐trihydroxy‐7 E ,9 E ,11 Z ,13 E ,17 Z ‐eicosapentaenoic acid), and resolvin E4 (RvE4; 5 S ,15 S ‐dihydroxy‐6 E ,8 Z ,11 Z ,13 E ,17 Z ‐eicosapentaenoic acid). Exogenous 15‐epi‐lipoxin A 5 , 15‐epi‐lipoxin A 4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15‐epi‐lipoxin A 5 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 A 5 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 A 5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.

15‐epi‐lipoxin A5 promotes neutrophil exit from exudates for clearance by splenic macrophages