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

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.

Automated summary

This study identifies the central role of IL-6 signaling in the regulation of LC3-associated phagocytosis (LAP) and its uncoupling in sepsis-induced immunoparalysis. IL-6 signaling orchestrates microtubule organization and dynamics to regulate ERK recruitment to the phagosome and LAPosome formation. Loss of IL-6 signaling specifically impairs ERK trafficking and LAP activation in sepsis, highlighting a molecular pathway underlying immunoparalysis.