Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis

Tonia Akoumianaki, Katerina Vaporidi, Eleni Diamantaki, Frédéric Pène, Remi Beau, Mark S Gresnigt, Marina Gkountzinopulou, Maria Venichaki, Elias Drakos, Jamel El-Benna, George Samonis, Kieu T T Le, Vinod Kumar, Dimitrios Georgopoulos, Frank L van de Veerdonk, Mihai G Netea, Jean-Paul Latge, Georgios Chamilos*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)
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Abstract

Immune deactivation of phagocytes is a central event in the pathogenesis of sepsis. Herein, we identify a master regulatory role of IL-6 signaling on LC3-associated phagocytosis (LAP) and reveal that uncoupling of these two processes during sepsis induces immunoparalysis in monocytes/macrophages. In particular, we demonstrate that activation of LAP by the human fungal pathogen Aspergillus fumigatus depends on ERK1/2-mediated phosphorylation of p47phox subunit of NADPH oxidase. Physiologically, autocrine IL-6/JAK2/Ninein axis orchestrates microtubule organization and dynamics regulating ERK recruitment to the phagosome and LC3(+) phagosome (LAPosome) formation. In sepsis, loss of IL-6 signaling specifically abrogates microtubule-mediated trafficking of ERK, leading to defective activation of LAP and impaired killing of bacterial and fungal pathogens by monocytes/macrophages, which can be selectively restored by IL-6 supplementation. Our work uncovers a molecular pathway linking IL-6 signaling with LAP and provides insight into the mechanisms underlying immunoparalysis in sepsis.

Original languageEnglish
Pages (from-to)1277-+
Number of pages23
JournalCell Host & Microbe
Volume29
Issue number8
Early online date1-Jul-2021
DOIs
Publication statusPublished - 11-Aug-2021

Keywords

  • JAK2 TYROSINE KINASE
  • NADPH OXIDASE
  • INDUCED IMMUNOSUPPRESSION
  • IFN-GAMMA
  • AUTOPHAGY
  • PHAGOSOMES
  • INFECTIONS
  • INHIBITOR
  • MICE
  • PHOSPHORYLATION

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