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Edited by Ruslan Medzhitov, Yale University, New Haven, CT, and approved April 14, 2020 (received for review October 22, 2019)
Significance
Sepsis remains a leading cause of death. New insights into its pathophysiology are likely to be key to the development of effective therapeutic strategies against sepsis. Given the role of GDF15 in metabolism regulation and in cachexia during late stages of cancer, features that also occur in sepsis, elucidation of the possible mechanistic role of GDF15 in sepsis is of great importance. We find that septic patients have very high levels of GDF15 in the peripheral blood, which correlate with clinical outcomes. Using Gdf15-deficient mice, we show that GDF15 plays a causal role in sepsis by delaying the local control of infection. These findings suggest GDF15 as a potential therapeutic target in sepsis secondary to a bacterial infection.
Abstract
Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growth and differentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand that signals through the TLR2-Myd88 axis for the secretion of GDF15, and that Gdf15-deficient mice are protected against abdominal sepsis due to increased chemokine CXC ligand 5 (CXCL5)-mediated recruitment of neutrophils into the peritoneum, leading to better local bacterial control. Our results identify GDF15 as a potential target to improve sepsis treatment. Its inhibition should increase neutrophil recruitment to the site of infection and consequently lead to better pathogen control and clearance.
Footnotes
↵1I.S., H.G.C., and A.N.-C. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: lmoita{at}igc.gulbenkian.pt.
Author contributions: L.F.M. designed research; I.S., H.G.C., A.N.-C., E.S., T.R.V., D. Pedroso, A.B., R.M., and D. Payen performed research; N.C., D. Payen, S.W., H.-S.Y., and M.S. contributed new reagents/analytic tools; I.S., H.G.C., A.N.-C., E.S., T.R.V., D. Pedroso, A.B., R.M., D. Payen, S.W., and L.F.M. analyzed data; and L.F.M. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1918508117/-/DCSupplemental.
- Copyright © 2020 the Author(s). Published by PNAS.
This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
CXCL5-mediated recruitment of neutrophils into the peritoneal cavity of Gdf15-deficient mice protects against abdominal sepsis
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