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. [Display omitted] •ERK signaling regulates NADPH-oxidase mediated activation of LAP•IL-6/JAK-2/Ninein axis controls microtubule-mediated ERK trafficking to the LAPosome•Loss of IL-6 signaling inhibits LAP, leading to impaired pathogen killing•IL-6 supplementation restores LAP defects and sepsis-induced immunoparalysis The mechanisms of sepsis-induced immunoparalysis are molecularly unexplored. Akoumianaki et al. discovered that loss of IL-6 signaling in monocytes/macrophages of sepsis patients and mice disrupts microtubule dynamics regulating ERK-dependent activation of LC3-associated phagocytosis (LAP) and results in impaired pathogen killing, which is reversible upon IL-6 supplementation. These findings have broad implications in pathogenesis and therapeutics of immune deactivation in sepsis.