| First Author | Akoumianaki T | Year | 2021 |
| Journal | Cell Host Microbe | Volume | 29 |
| Issue | 8 | Pages | 1277-1293.e6 |
| PubMed ID | 34214493 | Mgi Jnum | J:323598 |
| Mgi Id | MGI:6765665 | Doi | 10.1016/j.chom.2021.06.002 |
| Citation | Akoumianaki T, et al. (2021) Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis. Cell Host Microbe 29(8):1277-1293.e6 |
| abstractText | 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. |
