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

Akoumianaki, Tonia; Vaporidi, Katerina; Diamantaki, Eleni; Pène, Frédéric; Beau, Rémi; Gresnigt, Mark S.; Gkountzinopulou, Marina; Venichaki, Maria; Δράκος, Ηλίας; El-Benna, Jamel; Samonis, George; Le, Kieu; Kumar, Vinod; Georgopoulos, Dimitrios; Veerdonk, Frank L. van de; Netea, Mihai G.; Latgé, Jean‐Paul; Chamilos, Georgios

doi:10.1016/j.chom.2021.06.002

Cited by 33 publications

(24 citation statements)

References 74 publications

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“…As illustrated in Fig. 4a, the expression of LC3II was obviously upregulated by A. fumigatus conidia, which is in line with other findings in macrophages 22 . Intriguingly, increased LC3II expression was not suppressed by p38 or ERK inhibitors, but by JNK inhibitor (Fig.…”

Section: Involvement Of Jnk In a Fumigatus Conidia-induced Autophagy ...supporting

confidence: 90%

Involvement of JNK signaling in Aspergillus fumigatus-induced inflammatory factors release in bronchial epithelial cells

Chen¹,

Zhao²,

Li³

et al. 2023

Sci Rep

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Aspergillus fumigatus (A. fumigatus) is an important fungal pathogen and its conidia can be inhaled and interact with airway epithelial cells; however, the release of inflammatory factors from bronchial epithelial cells upon A. fumigatus infection and its regulation remained unclear. Here it was demonstrated that the release of IL-27, MCP-1 and TNF-α from BEAS-2B cells were upregulated upon stimulation by conidia, while mitogen-activated protein kinase signaling pathway was activated. Further, the inhibition of JNK, but not p38 and ERK, could inhibit inflammatory factors release and the LC3II formation in BEAS-2B cells induced by A. fumigatus conidia. In addition, an inhibitor of autophagy, bafilomycin A1 was able to significantly down-regulate the release of inflammatory factors in BEAS-2B cells upon A. fumigatus conidia, while rapamycin could reverse the effect of JNK inhibitor on IL-27 and TNF-α release. Taken together, these data demonstrated that JNK signal might play an important role in inflammatory factor release regulated by autophagy in bronchial epithelial cells against A. fumigatus infection.

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Section: Involvement Of Jnk In a Fumigatus Conidia-induced Autophagy ...supporting

confidence: 90%

Involvement of JNK signaling in Aspergillus fumigatus-induced inflammatory factors release in bronchial epithelial cells

Chen¹,

Zhao²,

Li³

et al. 2023

Sci Rep

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“…To devise HDTs effective against IA, we looked at the possible intracellular degradation pathways in innate immune phagocytes for conidia during the first stages of infection by analyzing GFP-Lc3 interaction with conidia. Autophagy pathways have been previously reported to be affected during immunosuppressive treatment against IA and in chronic granulomatous disease patients [ 52 , 57 ], and the autophagy-related pathway LAP has been linked to efficient fungal clearance of A. fumigatus conidia by macrophages [ 22 , 23 , 58 , 59 ]. During LAP, conidia are transported into single-membrane vesicles, which undergo a Reactive Oxygen Species (ROS) production burst and become decorated with LC3 for rapid degradation [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

Stimulating the autophagic-lysosomal axis enhances host defense against fungal infection in a zebrafish model of invasive Aspergillosis

et al. 2022

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The increasing prevalence of antifungal-resistant human pathogenic fungi, particularly azole-resistant Aspergillus fumigatus , is a life-threatening challenge to the immunocompromised population. Autophagy-related processes such as LC3-associated phagocytosis have been shown to be activated in the host response against fungal infection, but their overall effect on host resistance remains uncertain. To analyze the relevance of these processes in vivo , we used a zebrafish animal model of invasive Aspergillosis. To confirm the validity of this model to test potential treatments for this disease, we confirmed that immunosuppressive treatments or neutropenia rendered zebrafish embryos more susceptible to A. fumigatus . We used GFP-Lc3 transgenic zebrafish to visualize the autophagy-related processes in innate immune phagocytes shortly after phagocytosis of A. fumigatus conidia, and found that both wild-type and melanin-deficient conidia elicited Lc3 recruitment. In macrophages, we observed GFP-Lc3 accumulation in puncta after phagocytosis, as well as short, rapid events of GFP-Lc3 decoration of single and multiple conidia-containing vesicles, while neutrophils covered single conidia-containing vesicles with bright and long-lasting GFP-Lc3 signal. Next, using genetic and pharmacological stimulation of three independent autophagy-inducing pathways, we showed that the antifungal autophagy response improves the host survival against A. fumigatus infection, but only in the presence of phagocytes. Therefore, we provide proof-of-concept that stimulating the (auto)phagolysosomal pathways is a promising approach to develop host-directed therapies against invasive Aspergillosis, and should be explored further either as adjunctive or stand-alone therapy for drug-resistant Aspergillus infections. Abbreviations: DMSO: dimethyl sulfoxide; HR: hazard ratio; HDT: host-directed therapy; Hpf: hours post fertilization; IA: invasive Aspergillosis; LAP: LC3-associated phagocytosis; MTZ: metronidazole; PTU: N-phenylthiourea; ROS: reactive oxygen species.

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“…However, several reports have identified a link between the blockade of signals mediated by this critical cytokine in antifungal immunity and the risk of secondary fungal infections in critically ill patients with COVID-19 4,128,129 . The reasons for this may be many in view of the pleiotropic effects of IL-6; however, in fungal sepsis, loss of IL-6 signals was recently found to impair the activation of LC3-associated phagocytosis, a molecular process that is essential for fungal killing by monocytes and macrophages 130 . For this reason, clinical trials are required to address the benefit of the combined use of IL-6 receptor antagonists and antifungal prophylaxis in patients with severe COVID-19.…”

Section: Immunomodulationmentioning

confidence: 99%

COVID-19-associated fungal infections

et al. 2022

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Coronavirus disease 2019 (COVID-19)-associated invasive fungal infections are an important complication in a substantial number of critically ill, hospitalized patients with COVID-19. Three groups of fungal pathogens cause co-infections in COVID-19: Aspergillus , Mucorales and Candida species, including Candida auris . Here we review the incidence of COVID-19-associated invasive fungal infections caused by these fungi in low-, middle- and high-income countries. By evaluating the epidemiology, clinical risk factors, predisposing features of the host environment and immunological mechanisms that underlie the pathogenesis of these co-infections, we set the scene for future research and development of clinical guidance.

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

Cited by 33 publications

References 74 publications

Involvement of JNK signaling in Aspergillus fumigatus-induced inflammatory factors release in bronchial epithelial cells

Involvement of JNK signaling in Aspergillus fumigatus-induced inflammatory factors release in bronchial epithelial cells

Stimulating the autophagic-lysosomal axis enhances host defense against fungal infection in a zebrafish model of invasive Aspergillosis

COVID-19-associated fungal infections

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