Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis
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Publication year
2021Source
Cell Host & Microbe, 29, 8, (2021), pp. 1277-1293.e6ISSN
Publication type
Article / Letter to editor
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Organization
Internal Medicine
Journal title
Cell Host & Microbe
Volume
vol. 29
Issue
iss. 8
Page start
p. 1277
Page end
p. 1293.e6
Subject
Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences; Internal Medicine - Radboud University Medical CenterAbstract
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.
This item appears in the following Collection(s)
- Academic publications [245050]
- Electronic publications [132309]
- Faculty of Medical Sciences [93209]
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