LC3-associated phagocytosis: a crucial mechanism for antifungal host defence against<i>Aspergillus fumigatus</i>

Sprenkeler, Evelien G. G.; Gresnigt, Mark S.; Veerdonk, Frank L. van de

doi:10.1111/cmi.12616

Cited by 52 publications

(34 citation statements)

References 87 publications

(161 reference statements)

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“…We found that IFN-γ not only mediated LAP to A. fumigatus but also regulated NLRP3 activation during infection. The importance of LAP for fungal clearance (Kyrmizi et al., 2013, Martinez et al., 2015, Sprenkeler et al., 2016) and its subversion by fungal melanin (Akoumianaki et al., 2016) have been recently described. However, inflammation has to be controlled under microbial autophagy in the lung to prevent pulmonary overreaction (Kanayama et al., 2015a).…”

Section: Discussionmentioning

confidence: 99%

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Oikonomou

Moretti

Renga

et al. 2016

Cell Host & Microbe

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SummaryDefects in a form of noncanonical autophagy, known as LC3-associated phagocytosis (LAP), lead to increased inflammatory pathology during fungal infection. Although LAP contributes to fungal degradation, the molecular mechanisms underlying LAP-mediated modulation of inflammation are unknown. We describe a mechanism by which inflammation is regulated during LAP through the death-associated protein kinase 1 (DAPK1). The ATF6/C/EBP-β/DAPK1 axis activated by IFN-γ not only mediates LAP to Aspergillus fumigatus but also concomitantly inhibits Nod-like receptor protein 3 (NLRP3) activation and restrains pathogenic inflammation. In mouse models and patient samples of chronic granulomatous disease, which exhibit defective autophagy and increased inflammasome activity, IFN-γ restores reduced DAPK1 activity and dampens fungal growth. Additionally, in a cohort of hematopoietic stem cell-transplanted patients, a genetic DAPK1 deficiency is associated with increased inflammation and heightened aspergillosis susceptibility. Thus, DAPK1 is a potential drugable player in regulating the inflammatory response during fungal clearance initiated by IFN-γ.

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Section: Discussionmentioning

confidence: 99%

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Oikonomou

Moretti

Renga

et al. 2016

Cell Host & Microbe

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“…LAP-deficient mice develop an auto-inflammatory, lupus-like syndrome with aging, which can be recapitulated by chronic exposure to apoptotic cells [7]. Also, LAP-deficient mice fail to efficiently clear Aspergillus fumigatus infection [17, 89]. Thus, it is clear that defects in the LAP mechanism can have a breadth of immunological consequences.…”

Section: Lap Promotes Differential Outcomes During Immune Activationmentioning

confidence: 99%

LC3-Associated Phagocytosis and Inflammation

Heckmann

Boada-Romero

Cunha

et al. 2017

Journal of Molecular Biology

223

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LC3-associated phagocytosis (LAP) is a novel form of non-canonical autophagy where LC3 (microtubule-associated protein 1A/1B-light chain 3) is conjugated to phagosome membranes using a portion of the canonical autophagy machinery. The impact of LAP to immune regulation is best characterized in professional phagocytes, in particular macrophages, where LAP has instrumental roles in the clearance of extracellular particles including apoptotic cells and pathogens. Binding of dead cells via receptors present on the macrophage surface results in the translocation of the autophagy machinery to the phagosome and ultimately LC3 conjugation. These events promote a rapid form of phagocytosis that produces an “immunologically silent” clearance of the apoptotic cells. Consequences of LAP deficiency include a decreased capacity to clear dying cells and the establishment of a lupus-like autoimmune disease in mice. The ability of LAP to attenuate autoimmunity likely occurs through the dampening of pro-inflammatory signals upon engulfment of dying cells and prevention of autoantigen presentation to other immune cells. However, it remains unclear how LAP shapes both the activation and outcome of the immune response at the molecular level. Herein, we provide a detailed review of LAP and its known roles in the immune response and provide further speculation on the putative mechanisms by which LAP may regulate immune function, perhaps through the metabolic reprogramming and polarization of macrophages.

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“…nidulans Phagosomes containing Aspergillus conidia mature into a phagolysosome, a process that is characterized by fusion with endosomes and lysosomes. Over the past years it has been demonstrated that a fully functional LAP is required for inducing an optimal phagosome maturation of phagosomes containing A. fumigatus by monocyte/macrophages [19][20][21][22]. Moreover, cells from CGD patients recruit LC3 to Aspergillus-containing phagosomes less efficiently [7,20].…”

Section: Lc3-associated Phagocytosis Is Less Efficient Formentioning

confidence: 99%

Differential Kinetics of Aspergillus nidulans and Aspergillus fumigatus Phagocytosis

et al. 2017

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Invasive aspergillosis mainly occurs in immunocompromised patients and is commonly caused by Aspergillus fumigatus, while A.nidulans is rarely the causative agent. However, in chronic granulomatous disease (CGD) patients, A. nidulans is a frequent cause of invasive aspergillosis and is associated with higher mortality. Immune recognition of A. nidulans was compared to A. fumigatus to offer an insight into why A. nidulans infections are prevalent in CGD. Live cell imaging with J774A.1 macrophage-like cells and LC3-GFP-mCherry bone marrow-derived macrophages (BMDMs) revealed that phagocytosis of A. nidulans was slower compared to A. fumigatus. This difference could be attributed to slower migration of J774A.1 cells and a lower percentage of migrating BMDMs. In addition, delayed phagosome acidification and LC3-associated phagocytosis was observed with A. nidulans. Cytokine and oxidative burst measurements in human peripheral blood mononuclear cells revealed a lower oxidative burst upon challenge with A. nidulans. In contrast, A. nidulans induced significantly higher concentrations of cytokines. Collectively, our data demonstrate that A. nidulans is phagocytosed and processed at a slower rate compared to A. fumigatus, resulting in reduced fungal killing and increased germination of conidia. This slower rate of A. nidulans clearance may be permissive for overgrowth within certain immune settings.

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LC3-associated phagocytosis: a crucial mechanism for antifungal host defence againstAspergillus fumigatus

Cited by 52 publications

References 87 publications

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

LC3-Associated Phagocytosis and Inflammation

Differential Kinetics of Aspergillus nidulans and Aspergillus fumigatus Phagocytosis

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