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Nature Medicine 14, 392 - 398 (2008)
Published online: 30 March 2008 | doi:10.1038/nm1738

Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis

Adrian M Piliponsky1, Ching-Cheng Chen1,12, Toshihiko Nishimura2,12, Martin Metz3,4, Eon J Rios1, Paul R Dobner5, Etsuko Wada6,7, Keiji Wada6,7, Sherma Zacharias8, Uma M Mohanasundaram8, James D Faix1, Magnus Abrink9, Gunnar Pejler10, Ronald G Pearl8, Mindy Tsai1 & Stephen J Galli1,11

Sepsis is a complex, incompletely understood and often fatal disorder, typically accompanied by hypotension, that is considered to represent a dysregulated host response to infection. Neurotensin (NT) is a 13-amino-acid peptide that, among its multiple effects, induces hypotension. We find that intraperitoneal and plasma concentrations of NT are increased in mice after severe cecal ligation and puncture (CLP), a model of sepsis, and that mice treated with a pharmacological antagonist of NT, or NT-deficient mice, show reduced mortality during severe CLP. In mice, mast cells can degrade NT and reduce NT-induced hypotension and CLP-associated mortality, and optimal expression of these effects requires mast cell expression of neurotensin receptor 1 and neurolysin. These findings show that NT contributes to sepsis-related mortality in mice during severe CLP and that mast cells can lower NT concentrations, and suggest that mast cell–dependent reduction in NT levels contributes to the ability of mast cells to enhance survival after CLP.