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

Cell Host Microbe. 2021 Aug 11;29(8):1277-1293.e6. doi: 10.1016/j.chom.2021.06.002. Epub 2021 Jul 1.


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.

Keywords: Aspergillus fumigatus; IL-6; JAK; LAP; LC3-associated phagocytosis; NADPH oxidase; extracellular-signal-kinase regulated (ERK); microtubules; phagosome; sepsis; sepsis immunoparalysis.

MeSH terms

  • Aspergillus fumigatus / metabolism
  • Cytokines / metabolism
  • Cytoskeletal Proteins / metabolism
  • Humans
  • Interleukin-6 / metabolism*
  • Janus Kinase 2 / metabolism
  • Macrophages
  • Microtubule-Associated Proteins / metabolism*
  • Monocytes
  • Nuclear Proteins / metabolism
  • Phagocytes
  • Phagocytosis / immunology*
  • Phagocytosis / physiology
  • Sepsis / metabolism
  • Signal Transduction*


  • Cytokines
  • Cytoskeletal Proteins
  • Interleukin-6
  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • NIN protein, human
  • Nuclear Proteins
  • JAK2 protein, human
  • Janus Kinase 2