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Insights into Autophagic Machinery and Lysosomal Function in Cells Involved in the Psoriatic Immune-Mediated Inflammatory Cascade

Martyna Kuczyńska
Martyna Kuczyńska
, 
Marta Moskot
Marta Moskot
 oraz 
Magdalena Gabig-Cimińska
Magdalena Gabig-Cimińska
   | 27 lut 2024
Archivum Immunologiae et Therapiae Experimentalis's Cover Image
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Article Category: Review
Data publikacji: 27 lut 2024
Zakres stron: -
Otrzymano: 06 paź 2023
Przyjęty: 08 gru 2023
DOI: https://doi.org/10.2478/aite-2024-0005
Słowa kluczowe
© 2024 Martyna Kuczyńska et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Fig 1.

Therapeutic strategies targeting the dysfunctional ALP across different diseases. The figure serves as a comprehensive visual representation, elucidating the dual role of therapeutic approaches in modulating lysosomal action. The diversity of curative methods underscores the versatility and significance of targeting lysosomal functions in disease management. In lysosomal storage and neurodegenerative diseases, the goal is to improve lysosomal function, ensuring efficient cellular cleanup. In contrast, for cancer and certain autoimmune conditions such as Ps, the therapeutic objective is to alleviate or regulate heightened lysosomal activity that may contribute to disease pathology. ALP, autophagy–lysosomal pathway; Ps, psoriasis.
Therapeutic strategies targeting the dysfunctional ALP across different diseases. The figure serves as a comprehensive visual representation, elucidating the dual role of therapeutic approaches in modulating lysosomal action. The diversity of curative methods underscores the versatility and significance of targeting lysosomal functions in disease management. In lysosomal storage and neurodegenerative diseases, the goal is to improve lysosomal function, ensuring efficient cellular cleanup. In contrast, for cancer and certain autoimmune conditions such as Ps, the therapeutic objective is to alleviate or regulate heightened lysosomal activity that may contribute to disease pathology. ALP, autophagy–lysosomal pathway; Ps, psoriasis.

Fig 2.

Schematic representation of the ALP, detailing its main stages and highlighting key structural markers. The diagram begins with the endolysosomal pathway and the initiation of autophagy, progressing through the phases of EE and phagosome formation, leading to their respective maturation into an endolysosome and autolysosome, and culminating in the degradation phase within those structures. This visual representation underscores the intersection and the interconnection between the endolysosomal and autophagic pathways, illustrating the complex interplay and convergence of these two critical cellular processes. Each stage is meticulously annotated with relevant markers, which are presented against a distinct purple background for easy identification. ALP, autophagy–lysosomal pathway; ATG12, autophagy-related protein 12; DiRas3, distinct subgroup of the Ras family member 3; EEA1, early endosome antigen 1; EE, early endosome; LAMP1, lysosomal-associated membrane protein 1; LAMP2, lysosomal-associated membrane protein 2; LC3, microtubule-associated protein1A/1B-light chain 3; M6-PR, mannose-6-phosphate receptor; NBR1, neighbor of BRCA1 gene 1, autophagy cargo receptor; OPTN, optineurin; p62, autophagy receptor protein, also known as a multifunctional stress-inducible scaffold protein SQSTM1 (Sequestosome 1); Rab4, Rab5, Rab7, Rab9, members of the Ras superfamily of small Rab GTPases; RhoB, Ras homolog gene family, member B; TM7SF1, transmembrane 7 superfamily member 1 protein.
Schematic representation of the ALP, detailing its main stages and highlighting key structural markers. The diagram begins with the endolysosomal pathway and the initiation of autophagy, progressing through the phases of EE and phagosome formation, leading to their respective maturation into an endolysosome and autolysosome, and culminating in the degradation phase within those structures. This visual representation underscores the intersection and the interconnection between the endolysosomal and autophagic pathways, illustrating the complex interplay and convergence of these two critical cellular processes. Each stage is meticulously annotated with relevant markers, which are presented against a distinct purple background for easy identification. ALP, autophagy–lysosomal pathway; ATG12, autophagy-related protein 12; DiRas3, distinct subgroup of the Ras family member 3; EEA1, early endosome antigen 1; EE, early endosome; LAMP1, lysosomal-associated membrane protein 1; LAMP2, lysosomal-associated membrane protein 2; LC3, microtubule-associated protein1A/1B-light chain 3; M6-PR, mannose-6-phosphate receptor; NBR1, neighbor of BRCA1 gene 1, autophagy cargo receptor; OPTN, optineurin; p62, autophagy receptor protein, also known as a multifunctional stress-inducible scaffold protein SQSTM1 (Sequestosome 1); Rab4, Rab5, Rab7, Rab9, members of the Ras superfamily of small Rab GTPases; RhoB, Ras homolog gene family, member B; TM7SF1, transmembrane 7 superfamily member 1 protein.

Fig 3.

Molecular signaling involved in autophagy machinery and lysosomal biogenesis in Ps-affected human cell, particularly well known in KCs, and possible implications in Ps. Ca2+ is a prominent cell signaling mediator driving diverse cellular processes; it is absorbed from the extracellular space and/or mobilized from intracellular stores, such as the ER or lysosomes. Due to the ability to release the ions via dedicated channels, i.e., MCOLN1, in response to environmental cues, the lysosome is a key regulator of the cellular signaling pathway through mechanisms involving AMPK, mTORC1, CaM, and TFEB. Upon extracellular and ER Ca2+ flux, AMPK, transiently activated by CaM, partially inhibits mTORC1 in physiological conditions. Consequently, the mTORC1 effect on MCOLN1 and TFEB inhibition is diminished. MCOLN1 releases Ca2+ from the lysosome and activates CaM, which in turn triggers CaN. Activated CaN dephosphorylates TFEB, causing TFEB translocation to the nucleus, where it binds in the promoter region of genes, encoding proteins with lysosomal and autophagy function (CLEAR element). Deregulation of molecular mediators, i.e., Ca2+ influx and intracellular signaling reflected in Ps and upon the Ps inflammatory cascade, affects the majority of cellular processes, especially well known in KCs. These alterations in Ps KCs amplify the inflammatory immune feedback loop that initiates and sustains chronic inflammation in Ps. The disturbed Ca2+ level in KCs diminishes AMPK action, transiently activates mTORC1, inhibits ULK, impairs an autophagic flux and reduces the fusion of autophagosomes with lysosomes. In addition, during Ps inflammation, cells are continuously activated in response to a strong admission of cytokines and growth factors on the PI3K/Akt and MAPK/ERK pathways, promoting the active form of mTORC1. The downstream mediators in these cellular signaling pathways that inhibit autophagic flux and the exact target in the autophagic process remain unknown. Autophagy is a multistep process of a phagophore elongation, an autophagosome creation (with the conjugation of ATG12 to ATG5 and the conversion of LC3 I to LC3 II), proceeded by an autophagosome fusion with lysosomes to form autolysosomes, where the degradation of intracellular content and the recycling of macromolecule components appear. It seems that the transiently active mTORC1 facilitates the induction of autophagy in an initial phase. However, it reduces the lysosomal metabolism and levels and enzymatic activities in later periods, resulting in autophagy inhibition. This latter inhibition may be related to mTORC1-dependent TFEB nuclear translocation reduction, causing downregulation of genes involved in lysosomal biogenesis, autophagy machinery, immune responses, and metabolism. In parallel, NF-κB continuous activation associated with Ps inflammatory status determines the expression of immune response factors. Although the triggers and mediators, as well as the exact locations of their action during autophagy in Ps, are unknown, modulation by these factors of the autophagy process can contribute to immune-mediated inflammation and initiate or worsen the disease, with possible effects on proliferation and differentiation of KCs, epithelial barrier dysfunction, and inflammation. Created using BioRender.com. AhR, aryl hydrocarbon receptor; Akt, protein kinase B; AMP, antimicrobial peptide; AMPK, 5′AMP-activated protein kinase; ATG, autophagy-related protein; Ca2+, calcium ion; CaM, calmodulin; CaMKK2, Calcium–calmodulin-dependent protein kinase 2; CaN, calcineurin; CLEAR, coordinated lysosomal expression and regulation; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; KC, keratinocyte; LC3, microtubule-associated protein1A/1B-light chain 3; MAPK, mitogen-activated protein kinase; MCOLN1, mucolipin-1; mTORC1, mammalian target of rapamycin complex 1; NF-κB, nuclear factor kB; p38MAPK, p38 mitogen-activated protein kinase; PGRN, progranulin; PI3K, phosphoinositide 3-kinase; Ps, psoriasis; TFEB, transcription factor EB; ULK1, UNC-like autophagy activating kinase 1.
Molecular signaling involved in autophagy machinery and lysosomal biogenesis in Ps-affected human cell, particularly well known in KCs, and possible implications in Ps. Ca2+ is a prominent cell signaling mediator driving diverse cellular processes; it is absorbed from the extracellular space and/or mobilized from intracellular stores, such as the ER or lysosomes. Due to the ability to release the ions via dedicated channels, i.e., MCOLN1, in response to environmental cues, the lysosome is a key regulator of the cellular signaling pathway through mechanisms involving AMPK, mTORC1, CaM, and TFEB. Upon extracellular and ER Ca2+ flux, AMPK, transiently activated by CaM, partially inhibits mTORC1 in physiological conditions. Consequently, the mTORC1 effect on MCOLN1 and TFEB inhibition is diminished. MCOLN1 releases Ca2+ from the lysosome and activates CaM, which in turn triggers CaN. Activated CaN dephosphorylates TFEB, causing TFEB translocation to the nucleus, where it binds in the promoter region of genes, encoding proteins with lysosomal and autophagy function (CLEAR element). Deregulation of molecular mediators, i.e., Ca2+ influx and intracellular signaling reflected in Ps and upon the Ps inflammatory cascade, affects the majority of cellular processes, especially well known in KCs. These alterations in Ps KCs amplify the inflammatory immune feedback loop that initiates and sustains chronic inflammation in Ps. The disturbed Ca2+ level in KCs diminishes AMPK action, transiently activates mTORC1, inhibits ULK, impairs an autophagic flux and reduces the fusion of autophagosomes with lysosomes. In addition, during Ps inflammation, cells are continuously activated in response to a strong admission of cytokines and growth factors on the PI3K/Akt and MAPK/ERK pathways, promoting the active form of mTORC1. The downstream mediators in these cellular signaling pathways that inhibit autophagic flux and the exact target in the autophagic process remain unknown. Autophagy is a multistep process of a phagophore elongation, an autophagosome creation (with the conjugation of ATG12 to ATG5 and the conversion of LC3 I to LC3 II), proceeded by an autophagosome fusion with lysosomes to form autolysosomes, where the degradation of intracellular content and the recycling of macromolecule components appear. It seems that the transiently active mTORC1 facilitates the induction of autophagy in an initial phase. However, it reduces the lysosomal metabolism and levels and enzymatic activities in later periods, resulting in autophagy inhibition. This latter inhibition may be related to mTORC1-dependent TFEB nuclear translocation reduction, causing downregulation of genes involved in lysosomal biogenesis, autophagy machinery, immune responses, and metabolism. In parallel, NF-κB continuous activation associated with Ps inflammatory status determines the expression of immune response factors. Although the triggers and mediators, as well as the exact locations of their action during autophagy in Ps, are unknown, modulation by these factors of the autophagy process can contribute to immune-mediated inflammation and initiate or worsen the disease, with possible effects on proliferation and differentiation of KCs, epithelial barrier dysfunction, and inflammation. Created using BioRender.com. AhR, aryl hydrocarbon receptor; Akt, protein kinase B; AMP, antimicrobial peptide; AMPK, 5′AMP-activated protein kinase; ATG, autophagy-related protein; Ca2+, calcium ion; CaM, calmodulin; CaMKK2, Calcium–calmodulin-dependent protein kinase 2; CaN, calcineurin; CLEAR, coordinated lysosomal expression and regulation; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; KC, keratinocyte; LC3, microtubule-associated protein1A/1B-light chain 3; MAPK, mitogen-activated protein kinase; MCOLN1, mucolipin-1; mTORC1, mammalian target of rapamycin complex 1; NF-κB, nuclear factor kB; p38MAPK, p38 mitogen-activated protein kinase; PGRN, progranulin; PI3K, phosphoinositide 3-kinase; Ps, psoriasis; TFEB, transcription factor EB; ULK1, UNC-like autophagy activating kinase 1.

Overview of autophagic machinery and lysosomal function in cells, both structural (i.e., skin nonimmune cells) and immune (i.e., skin-associated and recirculating immune cells) cells, involved in the immune-mediated inflammatory cascade in Ps

Cell type ALP alterations in Ps Possible effects of autophagy disturbances leading to the development of the Ps phenotype References
Structural cells (skin nonimmune cells) KCs Upregulation of ATG5, ATG7, MAPK/ERK, mTORC1, NF-κB, NRF2, p62, and PI3K/Akt; Downregulation of AP1S3, CaN, and MCOLN1; Altered levels of LAMP1, LC3, TFEB, and lysosomal enzymes Cytokine production growth, inflammatory activation, hyperproliferation, differentiation disturbances, cathelicidin/LL-37 expression enhancement, PGRN expression increase Akinduro et al. 2016; Balato et al. 2014; Bocheńska et al. 2019; Buerger 2018; Dombrowski et al. 2011; Douroudis et al. 2012; Farag et al. 2019; Huang et al. 2015; Johansen et al. 2007; Klapan et al. 2021; Lee et al. 2011; Li et al. 2016; Mahil et al. 2016; Mercurio et al. 2021; Monteleon et al. 2018; Nada et al. 2020; Paushter et al. 2018; Salazar et al. 2020; Salskov-Iversen et al. 2011; Sánchez-Martín et al. 2019; Schönefuß et al. 2010; Sun et al. 2014; Wang et al. 2019b; Xue et al. 2022; Yin et al. 2018; Yu et al. 2007; Zhang and Zhang 2019
FBs Downregulation of ZFP36 Cytokine production growth Angiolilli et al. 2022
Immune cells (skin-associatedand recirculating immune cells) T cells Increased level of autophagy upon TCR stimulation; Reduced level of autophagy upon enhanced mTORC1 kinase activity Cytokine production growth, hyperproliferation, differentiation disturbances, Th population imbalance, TCR activation increase, apoptosis augmentation, cytokine secretion by multiplied DCs Benoit-Lizon et al. 2018; Botbol and Macian 2015; Bronietzki et al. 2015; Chung et al. 2009; Delgoffe et al. 2009, 2011; Deretic 2021; Dowling et al. 2018; Harris et al. 2008; Hirai et al. 2013; Hubbard et al. 2010; Jia et al. 2015; Kabat et al. 2016; Kiyono et al. 2009; Koga et al. 2014; Kopf et al. 2007; Kovacs et al. 2012; Lee et al. 2011; Liang et al. 2012; Matsuzawa et al. 2015; Mocholi et al. 2018; Murera et al. 2018; Parekh et al. 2013; Pua et al. 2007; Stockinger et al. 2007; Wei et al. 2016; Willinger and Flavell 2012
Macrophages Autophagy induction Polarization to M2 phenotype activation Germic et al. 2019; Jacquel et al. 2012; Liu et al. 2015
DCs Autophagy inhibition Cytokine production growth, inflammatory activation, Th17 differentiation increase, Th population imbalance, T cells responses via MHC I and MHC II pathways regulation Chung et al. 2009; Dengjel et al. 2005; Feng et al. 2019; Kasai et al. 2009; Loi et al. 2016; Merkley et al. 2018; Mintern et al. 2015; Schmid et al. 2007; Stockinger et al. 2007; Wenger et al. 2012
LCs Autophagy inhibition Cytokine production growth, Th17 differentiation increase, Th population imbalance Müller et al. 2020; Said et al. 2014; Zhang et al. 2022b
NKs n.d. Development and survival defect Wang et al. 2016
MCs n.d. Degranulation increase, KC hyperproliferation Ushio et al. 2011
VECs Autophagy induction; Downregulation of p38MAPK/mTOR pathway Cytokine production growth Zhou et al. 2023
B cells n.d. Inflammatory activation, differentiation disturbances, development defect, autoantigen presentation, immune tolerance disturbances, metabolic homeostasis fault Arbogast et al. 2019; Arnold et al. 2016; Raza and Clarke 2021; Sandoval et al. 2018
Granulocytes Altered lysosomal enzymes levels and activity Cytokines production growth, NETosis rise, proteolytic enzyme accumulation Germic et al. 2019; Gliński et al. 1984; Guo et al. 2019
eISSN:
1661-4917
Język:
Angielski
Częstotliwość wydawania:
Volume Open
Dziedziny czasopisma:
Medicine, Basic Medical Science, Biochemistry, Immunology, Clinical Medicine, other, Clinical Chemistry
Kanał RSS czasopisma