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Summary Breaching endothelial cells (ECs) is a decisive step in the migration of leukocytes from the vascular lumen to the extravascular tissue, but fundamental aspects of this response remain largely unknown. We have previously shown that neutrophils can exhibit abluminal-to-luminal migration through EC junctions within mouse cremasteric venules and that this response is elicited following reduced expression and/or functionality of the EC junctional adhesion molecule-C (JAM-C). Here we demonstrate that the lipid chemoattractant leukotriene B4 (LTB4) was efficacious at causing loss of venular JAM-C and promoting neutrophil reverse transendothelial cell migration (rTEM) in vivo. Local proteolytic cleavage of EC JAM-C by neutrophil elastase (NE) drove this cascade of events as supported by presentation of NE to JAM-C via the neutrophil adhesion molecule Mac-1. The results identify local LTB4-NE axis as a promoter of neutrophil rTEM and provide evidence that this pathway can propagate a local sterile inflammatory response to become systemic., Graphical Abstract, Highlights • Endogenous LTB4 mediates reduced expression of endothelial cell (EC) JAM-C in I-R • LTB4 can stimulate proteolytic cleavage of EC JAM-C by neutrophil elastase (NE) • Activation of a local LTB4-NE axis induces neutrophil reverse TEM in vivo • Activation of a local LTB4-NE axis can promote distant organ damage, The mechanisms and implications of aberrant modes of neutrophil transendothelial cell migration remain largely unknown. Here, Nourshargh and colleagues demonstrate that local leukotriene B4-induced proteolytic cleavage of endothelial JAM-C by neutrophil elastase promotes neutrophil reverse transendothelial cell migration back into the circulation and is decisive in dissemination of systemic inflammation.