Combined glucocorticoid resistance and hyperlactatemia contributes to lethal shock in sepsis

Jolien Vandewalle, Steven Timmermans, Ville Paakinaho, Lies Vancraeynest, Liza Dewyse, Tineke Vanderhaeghen, Charlotte Wallaeys, Lise Van Wyngene, Kelly Van Looveren, Louise Nuyttens, Melanie Eggermont, Sylviane Dewaele, Tiago R Velho, Luis F Moita, Sebastian Weis, Christoph Sponholz, Leo A van Grunsven, Mieke Dewerchin, Peter Carmeliet, Karolien De BosscherJohan Van de Voorde, Jorma J Palvimo, Claude Libert

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)
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Abstract

Sepsis is a potentially lethal syndrome resulting from a maladaptive response to infection. Upon infection, glucocorticoids are produced as a part of the compensatory response to tolerate sepsis. This tolerance is, however, mitigated in sepsis due to a quickly induced glucocorticoid resistance at the level of the glucocorticoid receptor. Here, we show that defects in the glucocorticoid receptor signaling pathway aggravate sepsis pathophysiology by lowering lactate clearance and sensitizing mice to lactate-induced toxicity. The latter is exerted via an uncontrolled production of vascular endothelial growth factor, resulting in vascular leakage and collapse with severe hypotension, organ damage, and death, all being typical features of a lethal form of sepsis. In conclusion, sepsis leads to glucocorticoid receptor failure and hyperlactatemia, which collectively leads to a lethal vascular collapse.

Original languageEnglish
Pages (from-to)1763-1776.e5
Number of pages14
JournalCell Metabolism
Volume33
Issue number9
DOIs
Publication statusPublished - 7 Sep 2021

Bibliographical note

Copyright © 2021 Elsevier Inc. All rights reserved.

Keywords

  • glucocorticoid resistance
  • hyperlactatemia
  • metabolism
  • sepsis
  • shock

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