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

Nature Medicine volume 14, pages 392–398 (2008)Cite this article

Abstract

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.

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Figure 1: NT levels are increased and contribute to mortality after CLP in mice.
Figure 2: Evidence that NT can contribute to mortality after CLP in wild-type or KitW/W-v MC-deficient mice.
Figure 3: MCs reduce peritoneal NT concentrations and NT-induced hypotension.
Figure 4: NLN contributes to the ability of MCs to reduce amount of NT and NT-induced hypotension.
Figure 5: MCs can degrade NT in the absence of extensive degranulation.
Figure 6: MC expression of Ntsr1 is required for optimal MC-dependent reduction of NT-induced hypotension and enhancement of survival after CLP.

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Acknowledgements

We thank A. Xu and D. Lepard for technical assistance, M. Krupa-Plonowska and G. O'Riordan for their assistance with the collection of human blood samples, A. Patterson and R. Agrawal for the use of equipment to measure blood pressure and J. Kalesnikoff for critical reading of the manuscript. We thank B. Vincent (Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique, Valbonne, France) for providing antibodies against NLN, M. Gurish (Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts) for providing antibodies to mMCP-4 and mMCP-5, R. Carraway (University of Massachusetts Medical School, Worcester, Massachusetts) for providing antibodies to Ntsr1, V. Dive (Commissariat a L'Ennergie Atomique, Saclay, France) for providing phosphodiepryl-03, a NLN inhibitor that can be used with living cells, S. Wilk (Mount Sinai School of Medicine, New York) for providing CFp-Ala-Ala-Phe-pAB, L. Van Parijs (Massachusetts Institute of Technology) for providing pLentiLox 3.7 (pLL3.7), D. Gully (Sanofi-Synthelabo Recherche, Tolouse Cedex, France) for providing SR142948A and Amgen for the gifts of rat rSCF, human rSCF164 and human rIL-6. This work was supported by United States Public Health Science Grants (to S.J.G. and C.-C.C.), and by a fellowship from Deutsche Forschungsgemeinschaft (to M.M.).

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Author notes

  1. Ching-Cheng Chen and Toshihiko Nishimura: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Adrian M Piliponsky, Ching-Cheng Chen, Eon J Rios, James D Faix, Mindy Tsai & Stephen J Galli

  2. Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305, USA.,

    Toshihiko Nishimura

  3. Department of Dermatology and Allergy, Allergie-Centrum-Charité, Charité-Universitätsmedizin Berlin, Berlin, D-10117, Germany

    Martin Metz

  4. Department of Dermatology, University Hospital Mainz, Mainz, 55131, Germany

    Martin Metz

  5. Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, 01655, Massachusetts, USA

    Paul R Dobner

  6. Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan

    Etsuko Wada & Keiji Wada

  7. CREST, Japan Science and Technology Agency, Kawaguchi, 322-0012, Saitama, Japan

    Etsuko Wada & Keiji Wada

  8. Department of Anesthesiology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Sherma Zacharias, Uma M Mohanasundaram & Ronald G Pearl

  9. Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, SE-751 05, Sweden

    Magnus Abrink

  10. Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, 750 07, Sweden

    Gunnar Pejler

  11. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, 94305, California, USA

    Stephen J Galli

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Contributions

A.M.P., C.-C.C., T.N., E.J.R., P.R.D., J.D.F., R.G.P., M.T. and S.J.G. designed research; A.M.P., C.-C.C., T.N., M.M., E.J.R., S.Z. and U.M.M. performed research; A.M.P., C.-C.C., T.N., E.J.R., P.R.D., E.W., K.W., M.A., G.P., R.G.P., M.T. and S.J.G. analyzed data; A.M.P. and S.J.G. wrote the manuscript and C.-C.C., T.N., M.M., E.J.R., P.R.D., E.W., K.W., S.Z., U.M.M., J.D.F., M.A., G.P., R.G.P. and M.T. contributed to the revision and approval of the manuscript.

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Correspondence to Stephen J Galli.

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Competing interests

Some authors of this manuscript (A.M.P., M.T. and S.J.G.) have filed a US patent entitled “Neurotensin as a marker and therapeutic target for sepsis” (patent 11/875,710). If issued, this patent will be assigned to Stanford University.

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Piliponsky, A., Chen, CC., Nishimura, T. et al. Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis. Nat Med 14, 392–398 (2008). https://doi.org/10.1038/nm1738

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