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The Autophagic Process in Human Physiology and Pathogenesis

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Autophagy".

Deadline for manuscript submissions: closed (25 May 2023) | Viewed by 34584

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Special Issue Editors

Dr. Simone Patergnani

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Guest Editor

Department of Medical Sciences, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, 44121 Ferrara, Italy
Interests: autophagy; mitophagy; neurodegeneration; cancer; mitochondria; calcium; endoplasmic reticulum; apoptosis; chemotherapy; mitochondrial diseases
Special Issues, Collections and Topics in MDPI journals

Dr. Alberto Danese

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Guest Editor

Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
Interests: autophagy; calcium; mitochondrial disorders; cancer

Special Issue Information

Dear Colleagues,

Autophagy, a conserved “self-eating” recycling process, is enticing remarkable research efforts, especially in recent years. Although it was initially considered a physiological process, useful for the turnover of proteins and organelles, many new data are shedding light on molecular details involved in the autophagic process, highlighting how its perturbation can lead to the onset of various human diseases, including cancer, neurodegeneration, metabolic disorders and infections. Refining knowledge regarding the autophagic signaling pathway will help to better describe the pathogenesis of these diseases, and the modulation of this crucial degradative process is regarded as a new therapeutic opportunity for future treatments.

This Special Issue aims to summarize the current knowledge on the central role that the autophagic process plays in maintaining physiological conditions and how its perturbation could be harmful.

We encourage you to submit research articles as well as review articles that investigate aspects relevant to physiological and pathological autophagic events, including new therapeutic approaches proposals and methods measuring the different autophagic forms.

Potential topics include but are not limited to tissue homeostasis, metabolism, crosstalk between autophagy and other signaling pathways, proliferation, and selective forms of autophagy.

We look forward to your contributions.

Dr. Simone Patergnani
Dr. Alberto Danese
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

autophagy
pathology
physiology
therapy
methods

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Published Papers (10 papers)

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Research

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21 pages, 6670 KiB

Open AccessArticle

Nrf2 Deficiency Exacerbated CLP-Induced Pulmonary Injury and Inflammation through Autophagy- and NF-κB/PPARγ-Mediated Macrophage Polarization

by Jing Luo, Jin Wang, Jing Zhang, Aming Sang, Xujun Ye, Zhenshun Cheng and Xinyi Li

Cells 2022, 11(23), 3927; https://doi.org/10.3390/cells11233927 - 4 Dec 2022

Cited by 30 | Viewed by 4828

Abstract

The balance between M1 and M2 macrophage polarization is involved in the regulation of pulmonary inflammation. Nuclear factor erythroid-derived 2-like 2 (Nfe2l2, also known as Nrf2), a nuclear transcription factor, is reported to play protective roles in acute lung injury (ALI) and inflammation, and increasing evidence indicates that the protective effects of Nrf2 are closely related to autophagy. This study aimed to explore whether Nrf2 is involved in sepsis-induced acute pulmonary injury and inflammation and in the role of macrophage polarization in the process. In the present study, sepsis patients, an Nrf2 knockout mouse that underwent cecal ligation and puncture (CLP), and lipopolysaccharide (LPS)-treated macrophage cell lines were employed to investigate the potential functions of Nrf2 in sepsis-induced lung injury and the underlying mechanisms. Clinical studies showed that the NRF2 mRNA level was inversely correlated with pulmonary inflammation and disease severity in patients with sepsis. Analyses in a CLP-treated Nrf2 knockout mouse model indicated that an Nrf2 deficiency promoted a CLP-induced increase in M1 macrophage polarization and apoptosis and inhibited CLP-induced upregulation of the autophagy level in lung tissues. Experiments in RAW264.7 cells revealed that Nrf2 overexpression inhibited M1 macrophage polarization but promoted M2 macrophage polarization by improving the autophagy, and Nrf2 overexpression promoted PPARγ but inhibited NF-κB nuclear translocation. In conclusion, these results indicate that Nrf2 plays a protective role in sepsis-induced pulmonary injury and inflammation through the regulation of autophagy- and NF-κB/PPARγ-mediated macrophage polarization. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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17 pages, 3710 KiB

Open AccessArticle

The ATG8 Family Proteins GABARAP and GABARAPL1 Target Antigen to Dendritic Cells to Prime CD4⁺ and CD8⁺ T Cells

by Leïla Fonderflick, Timothée Baudu, Olivier Adotévi, Michaël Guittaut, Pascale Adami and Régis Delage-Mourroux

Cells 2022, 11(18), 2782; https://doi.org/10.3390/cells11182782 - 6 Sep 2022

Cited by 3 | Viewed by 2431

Abstract

Vaccine therapy is a promising method of research to promote T cell immune response and to develop novel antitumor immunotherapy protocols. Accumulating evidence has shown that autophagy is involved in antigen processing and presentation to T cells. In this work, we investigated the potential role of GABARAP and GABARAPL1, two members of the autophagic ATG8 family proteins, as surrogate tumor antigen delivery vectors to prime antitumor T cells. We showed that bone marrow-derived dendritic cells, expressing the antigen OVALBUMIN (OVA) fused with GABARAP or GABARAPL1, were able to prime OVA-specific CD4⁺ T cells in vitro. Interestingly, the fusion proteins were also degraded by the proteasome pathway and the resulting peptides were presented by the MHC class I system. We then asked if the aforementioned fusion proteins could improve tumor cell immunogenicity and T cell priming. The B16-F10 melanoma was chosen as the tumor cell line to express the fusion proteins. B16-F10 cells that expressed the OVA-ATG8 fused proteins stimulated OVA-specific CD8⁺ T cells, but demonstrated no CD4⁺ T cell response. In the future, these constructions may be used in vaccination trials as potential candidates to control tumor growth. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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14 pages, 5876 KiB

Open AccessArticle

Modulation of MAPK- and PI3/AKT-Dependent Autophagy Signaling by Stavudine (D4T) in PBMC of Alzheimer’s Disease Patients

by Francesca La Rosa, Chiara Paola Zoia, Chiara Bazzini, Alessandra Bolognini, Marina Saresella, Elisa Conti, Carlo Ferrarese, Federica Piancone, Ivana Marventano, Daniela Galimberti, Chiara Fenoglio, Elio Scarpini and Mario Clerici

Cells 2022, 11(14), 2180; https://doi.org/10.3390/cells11142180 - 12 Jul 2022

Cited by 14 | Viewed by 3005

Abstract

Background: Aβ₄₂ deposition plays a pivotal role in AD pathogenesis by inducing the activation of microglial cells and neuroinflammation. This process is antagonized by microglia-mediated clearance of Aβ plaques. Activation of the NLRP3 inflammasome is involved in neuroinflammation and in the impairments of Aβ-plaque clearance. On the other hand, stavudine (D4T) downregulates the NLRP3 inflammasome and stimulates autophagy-mediated Aβ-clearing in a THP-1-derived macrophages. Methods: We explored the effect of D4T on Aβ autophagy in PBMC from AD patients that were primed with LPS and stimulated with Aβ oligomers in the absence/presence of D4T. We analyzed the NLRP3 activity by measuring NLRP3-ASC complex formation by AMNIS FlowSight and pro-inflammatory cytokine (IL-1β, IL-18 and Caspase-1) production by ELISA. The phosphorylation status of p38, ERK, AKT, p70, and the protein expression of CREB, LAMP2A, beclin-1, Caspase-3 and Bcl2 were analyzed by Western blot. Results: Data showed that D4T: (1) downregulates NLRP3 inflammasome activation and the production of down-stream pro-inflammatory cytokines in PBMC; (2) stimulates the phosphorylation of AKT, ERK and p70 as well as LAMP2A, beclin-1 and Bcl2 expression and reduces Caspase-3 expression, suggesting an effect of this compound on autophagy; (3) increases phospho-CREB, which is a downstream target of p-ERK and p-AKT, inducing anti-inflammatory cytokine production and resulting in a possible decrease of Aβ-mediated cytotoxicity; and (4) reduces the phosphorylation of p38, a protein involved in the production of pro-inflammatory cytokines and tau hyperphosphorylation. Conclusions: D4T reduces the activation of the NLRP3 inflammasome, and it might stimulate autophagy as well as the molecular mechanism that modulates Aβ cytotoxicity, and D4T might reduce inflammation in the cells of AD patients. It could be very interesting to check the possible beneficial effects of D4T in the clinical scenario. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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16 pages, 2926 KiB

Open AccessArticle

Hypoxia Induces Autophagy in Human Dendritic Cells: Involvement of Class III PI3K/Vps34

by Sara Monaci, Federica Coppola, Daniela Rossi, Gaia Giuntini, Irene Filippi, Giuseppe Marotta, Silvano Sozzani, Fabio Carraro and Antonella Naldini

Cells 2022, 11(10), 1695; https://doi.org/10.3390/cells11101695 - 19 May 2022

Cited by 9 | Viewed by 2438

Abstract

Hypoxia is a component of both physiological and pathological conditions, including inflammation, solid tumors, and lymphoid tissues, where O₂ demand is not balanced by O₂ supply. During their lifespan, dendritic cells (DCs) are exposed to different pO₂ and activate different adaptive responses, including autophagy, to preserve their viability and functions. Autophagy plays multiple roles in DC physiology. Very recently, we demonstrated that hypoxia shapes autophagy in DCs upon their differentiation state. Here, we proposed a role for PI3Ks, and especially class III PI3K/Vps34, that could be relevant in hypoxia-induced autophagy, in either immature or mature DCs. Hypoxia inhibited mTOR phosphorylation and activated a pro-autophagic program. By using different pharmacological inhibitors, we demonstrated that hypoxia-induced autophagy was mediated by PI3Ks, especially by Vps34. Furthermore, Vps34 expression was enhanced by LPS, a TLR4 ligand, along with the promotion of autophagy under hypoxia. The Vps34 inhibitor, SAR405, abolished hypoxia-induced autophagy, inhibited pro-survival signaling and viability, and increased the expression of proinflammatory cytokines. Our results underlined the impact of autophagy in the maintenance of DC homeostasis at both cell survival and inflammatory response levels, therefore, contributing to a better understanding of the significance of autophagy in DC physiology and pathology. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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11 pages, 12454 KiB

Open AccessArticle

Modulation of Intestinal Epithelial Permeability via Protease-Activated Receptor-2-Induced Autophagy

by Yuju Kim, Yunna Lee, Gwangbeom Heo, Sihyun Jeong, Soyeong Park, Jin-Wook Yoo, Yunjin Jung and Eunok Im

Cells 2022, 11(5), 878; https://doi.org/10.3390/cells11050878 - 3 Mar 2022

Cited by 12 | Viewed by 3147

Abstract

Protease-activated receptor 2 (PAR2) alleviates intestinal inflammation by upregulating autophagy. PAR2 also modulates tight junctions through β-arrestin signaling. Therefore, we investigated the effect of PAR2-induced autophagy on intestinal epithelial tight junctions and permeability. RT-PCR, Western blot analysis, and immunoprecipitation were performed to investigate the underlying molecular mechanisms by which PAR2 regulates autophagy and intestinal epithelial tight junctions. Inhibition of PAR2 by GB83, a PAR2 antagonist, decreased the expression of autophagy-related and tight-junction-related factors in Caco-2 cells. Moreover, inhibition of PAR2 decreased intestinal transepithelial electrical resistance. When PAR2 was activated, intestinal permeability was maintained, but when autophagy was suppressed by chloroquine, intestinal permeability was significantly increased. In addition, the prolongation of ERK1/2 phosphorylation by PAR2–ERK1/2–β-arrestin assembly was reduced under autophagy inhibition conditions. Therefore, PAR2 induces autophagy to regulate intestinal epithelial permeability, suggesting that it is related to the β-arrestin–ERK1/2 pathway. In conclusion, regulating intestinal epithelial permeability through PAR2-induced autophagy can help maintain mucosal barrier integrity. Therefore, these findings suggest that the regulation of PAR2 can be a suitable strategy to treat intestinal diseases caused by permeability dysfunction. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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15 pages, 3158 KiB

Open AccessArticle

Direct Interaction of ATP7B and LC3B Proteins Suggests a Cooperative Role of Copper Transportation and Autophagy

by Supansa Pantoom, Adam Pomorski, Katharina Huth, Christina Hund, Janine Petters, Artur Krężel, Andreas Hermann and Jan Lukas

Cells 2021, 10(11), 3118; https://doi.org/10.3390/cells10113118 - 10 Nov 2021

Cited by 15 | Viewed by 3192

Abstract

Macroautophagy/autophagy plays an important role in cellular copper clearance. The means by which the copper metabolism and autophagy pathways interact mechanistically is vastly unexplored. Dysfunctional ATP7B, a copper-transporting ATPase, is involved in the development of monogenic Wilson disease, a disorder characterized by disturbed copper transport. Using in silico prediction, we found that ATP7B contains a number of potential binding sites for LC3, a central protein in the autophagy pathway, the so-called LC3 interaction regions (LIRs). The conserved LIR3, located at the C-terminal end of ATP7B, was found to directly interact with LC3B in vitro. Replacing the two conserved hydrophobic residues W1452 and L1455 of LIR3 significantly reduced interaction. Furthermore, autophagy was induced in normal human hepatocellular carcinoma cells (HepG2) leading to enhanced colocalization of ATP7B and LC3B on the autophagosome membranes. By contrast, HepG2 cells deficient of ATP7B (HepG2 ATP7B^−/−) showed autophagy deficiency at elevated copper condition. This phenotype was complemented by heterologous ATP7B expression. These findings suggest a cooperative role of ATP7B and LC3B in autophagy-mediated copper clearance. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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12 pages, 14040 KiB

Open AccessArticle

Phagocyte Chemoattraction Is Induced through the Mcp-1–Ccr2 Axis during Efferocytosis

by Sang-Ah Lee, Deokhwan Kim, Chanhyuk Min, Byeongjin Moon, Juyeon Lee, Hyunji Moon, Susumin Yang, Chang Sup Lee, Gwangrog Lee and Daeho Park

Cells 2021, 10(11), 3115; https://doi.org/10.3390/cells10113115 - 10 Nov 2021

Cited by 3 | Viewed by 2811

Abstract

Apoptotic cells generated during development and for tissue homeostasis are swiftly and continuously removed by phagocytes via a process called efferocytosis. Efficient efferocytosis can be achieved via transcriptional modulation in phagocytes that have engulfed apoptotic cells. However, such modulation and its effect on efferocytosis are not completely understood. Here, we report that phagocytes are recruited to apoptotic cells being cleared through the Mcp-1–Ccr2 axis, which facilitates clearance of apoptotic cells. We identified Mcp-1 as a modulated transcript using a microarray and found that Mcp-1 secretion was augmented in phagocytes engulfing apoptotic cells. This augmented Mcp-1 secretion was impaired by blocking phagolysosomal degradation of apoptotic cells. Conditioned medium from wild type (WT) phagocytes promoted cell migration, but that from Mcp-1^−/− phagocytes did not. In addition, blockade of Ccr2, the receptor for Mcp-1, abrogated cell migration to conditioned medium from phagocytes incubated with apoptotic cells. The intrinsic efferocytosis activity of Mcp-1⁻^/− and Ccr2⁻^/− phagocytes was unaltered, but clearance of apoptotic cells was less efficient in the peritoneum of Mcp-1⁻^/− and Ccr2⁻^/− mice than in that of WT mice because fewer Ccr2-positive phagocytes were recruited. Taken together, our findings demonstrate a mechanism by which not only apoptotic cells but also phagocytes induce chemoattraction to recruit phagocytes to sites where apoptotic cells are cleared for efficient efferocytosis. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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Review

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33 pages, 3045 KiB

Open AccessReview

Neuronal Autophagy: Regulations and Implications in Health and Disease

by Caroline Liénard, Alexandre Pintart and Pascale Bomont

Cells 2024, 13(1), 103; https://doi.org/10.3390/cells13010103 - 4 Jan 2024

Cited by 7 | Viewed by 3922

Abstract

Autophagy is a major degradative pathway that plays a key role in sustaining cell homeostasis, integrity, and physiological functions. Macroautophagy, which ensures the clearance of cytoplasmic components engulfed in a double-membrane autophagosome that fuses with lysosomes, is orchestrated by a complex cascade of events. Autophagy has a particularly strong impact on the nervous system, and mutations in core components cause numerous neurological diseases. We first review the regulation of autophagy, from autophagosome biogenesis to lysosomal degradation and associated neurodevelopmental/neurodegenerative disorders. We then describe how this process is specifically regulated in the axon and in the somatodendritic compartment and how it is altered in diseases. In particular, we present the neuronal specificities of autophagy, with the spatial control of autophagosome biogenesis, the close relationship of maturation with axonal transport, and the regulation by synaptic activity. Finally, we discuss the physiological functions of autophagy in the nervous system, during development and in adulthood. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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21 pages, 1817 KiB

Open AccessReview

Endothelial Autophagy Dysregulation in Diabetes

by Yann Salemkour and Olivia Lenoir

Cells 2023, 12(6), 947; https://doi.org/10.3390/cells12060947 - 21 Mar 2023

Cited by 8 | Viewed by 3083

Abstract

Diabetes mellitus is a major public health issue that affected 537 million people worldwide in 2021, a number that is only expected to increase in the upcoming decade. Diabetes is a systemic metabolic disease with devastating macro- and microvascular complications. Endothelial dysfunction is a key determinant in the pathogenesis of diabetes. Dysfunctional endothelium leads to vasoconstriction by decreased nitric oxide bioavailability and increased expression of vasoconstrictor factors, vascular inflammation through the production of pro-inflammatory cytokines, a loss of microvascular density leading to low organ perfusion, procoagulopathy, and/or arterial stiffening. Autophagy, a lysosomal recycling process, appears to play an important role in endothelial cells, ensuring endothelial homeostasis and functions. Previous reports have provided evidence of autophagic flux impairment in patients with type I or type II diabetes. In this review, we report evidence of endothelial autophagy dysfunction during diabetes. We discuss the mechanisms driving endothelial autophagic flux impairment and summarize therapeutic strategies targeting autophagy in diabetes. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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20 pages, 2696 KiB

Open AccessReview

Regulation of Cellular Ribonucleoprotein Granules: From Assembly to Degradation via Post-translational Modification

by Pureum Jeon, Hyun-Ji Ham, Semin Park and Jin-A Lee

Cells 2022, 11(13), 2063; https://doi.org/10.3390/cells11132063 - 29 Jun 2022

Cited by 10 | Viewed by 4558

Abstract

Cells possess membraneless ribonucleoprotein (RNP) granules, including stress granules, processing bodies, Cajal bodies, or paraspeckles, that play physiological or pathological roles. RNP granules contain RNA and numerous RNA-binding proteins, transiently formed through the liquid–liquid phase separation. The assembly or disassembly of numerous RNP granules is strongly controlled to maintain their homeostasis and perform their cellular functions properly. Normal RNA granules are reversibly assembled, whereas abnormal RNP granules accumulate and associate with various neurodegenerative diseases. This review summarizes current studies on the physiological or pathological roles of post-translational modifications of various cellular RNP granules and discusses the therapeutic methods in curing diseases related to abnormal RNP granules by autophagy. Full article

(This article belongs to the Special Issue The Autophagic Process in Human Physiology and Pathogenesis)

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