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Regulation of Cytokine Signaling in Immunity

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

Deadline for manuscript submissions: closed (15 October 2020) | Viewed by 80794

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Dr. Dirk Schmidt-Arras

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Guest Editor

Institute of Biochemistry at the University of Kiel, 24118 Kiel, Germany
Interests: inflammatory cytokine signalling; tumorigenesis and metastasis; proteolytic control of paracrine signalling routes

Special Issue Information

Dear Colleagues,

Cytokines are a family of small proteins that regulate a plethora of biological functions, in particular in the innate and adaptive immune system. In the immune system, cytokines induce proliferation and differentiation of leukocytes, but are also crucial for the activation and inactivation of inflammatory cells. Furthermore, cytokines can have dual functions by additionally regulating tissue homeostasis and regeneration. Overwhelming activity of cytokines or loss-of-function is involved in several pathologies including sepsis, chronic inflammation, cancer and immunodeficiency. Therefore, cytokine signalling has to be tightly regulated and can occur at multiple levels, including proteolytic control of cytokine release and receptor shedding, generation of cytokine binding proteins and intracellular negative feedback signalling. Cytokine-targeting therapies hold great promise for the treatment of inflammatory disease and cancer.

This special issue aims to gather expert articles on different aspects of how to regulate cytokine signalling in immunity. I therefore invite you to submit original research articles or reviews.

Dr. Dirk Schmidt-Arras
Guest Editor

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Keywords

cytokine
chemokine
signaling
immunity
inflammation
cancer
microbiome

Published Papers (14 papers)

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Research

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12 pages, 3597 KiB

Open AccessArticle

Priming of the cGAS-STING-TBK1 Pathway Enhances LPS-Induced Release of Type I Interferons

by Alessandra Tesser, Giulia Maria Piperno, Alessia Pin, Elisa Piscianz, Valentina Boz, Federica Benvenuti and Alberto Tommasini

Cells 2021, 10(4), 785; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10040785 - 01 Apr 2021

Cited by 15 | Viewed by 4640

Abstract

Cytoplasmic nucleic acids sensing through cGAS-STING-TBK1 pathway is crucial for the production of antiviral interferons (IFNs). IFN production can also be induced by lipopolysaccharide (LPS) stimulation through Toll-like receptor 4 (TLR4) in appropriate conditions. Of note, both IFN production and dysregulated LPS-response could play a role in the pathogenesis of Systemic Lupus Erythematosus (SLE). Indeed, LPS can trigger SLE in lupus-prone mice and bacterial infections can induce disease flares in human SLE. However, the interactions between cGAS and TLR4 pathways to IFNs have been poorly investigated. To address this issue, we studied LPS-stimulation in cellular models with a primed cGAS-STING-TBK1 pathway. cGAS-stimulation was naturally sustained by undigested self-nucleic acids in fibroblasts from DNase2-deficiency interferonopathy, whilst it was pharmacologically obtained by cGAMP-stimulation in THP1 cells and murine bone marrow-derived dendritic cells. We showed that cells with a primed cGAS-STING-TBK1 pathway displayed enhanced IFNs production after TLR4-challenge. STING-inhibition did not affect IFN production after LPS alone, but prevented the amplified IFN production in cGAMP-primed cells, suggesting that functional STING is required for priming-dependent enhancement. Furthermore, we speculated that an increased PIK3AP1 expression in DNase2-deficient fibroblasts may link cGAMP-priming with increased LPS-induced IFN production. We showed that both the hyper-expression of PIK3API and the enhanced LPS-induced IFN production can be contrasted by STING inhibitors. Our results may explain how bacterial LPS can synergize with cGAS-pathway in promoting the development of SLE-like autoimmunity. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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16 pages, 3997 KiB

Open AccessArticle

GRIM19 Impedes Obesity by Regulating Inflammatory White Fat Browning and Promoting Th17/Treg Balance

by JooYeon Jhun, Jin Seok Woo, Seung Hoon Lee, Jeong-Hee Jeong, KyungAh Jung, Wonhee Hur, Seon-Yeong Lee, Jae Yoon Ryu, Young-Mee Moon, Yoon Ju Jung, Kyo Young Song, Kiyuk Chang, Seung Kew Yoon, Sung-Hwan Park and Mi-La Cho

Cells 2021, 10(1), 162; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010162 - 15 Jan 2021

Cited by 8 | Viewed by 3015

Abstract

Obesity, a condition characterized by excessive accumulation of body fat, is a metabolic disorder related to an increased risk of chronic inflammation. Obesity is mediated by signal transducer and activator of transcription (STAT) 3, which is regulated by genes associated with retinoid-interferon-induced mortality (GRIM) 19, a protein ubiquitously expressed in various human tissues. In this study, we investigated the role of GRIM19 in diet-induced obese C57BL/6 mice via intravenous or intramuscular administration of a plasmid encoding GRIM19. Splenocytes from wild-type and GRIM19-overexpressing mice were compared using enzyme-linked immunoassay, real-time polymerase chain reaction, Western blotting, flow cytometry, and histological analyses. GRIM19 attenuated the progression of obesity by regulating STAT3 activity and enhancing brown adipose tissue (BAT) differentiation. GRIM19 regulated the differentiation of mouse-derived 3T3-L1 preadipocytes into adipocytes, while modulating gene expression in white adipose tissue (WAT) and BAT. GRIM19 overexpression reduced diet-induced obesity and enhanced glucose and lipid metabolism in the liver. Moreover, GRIM19 overexpression reduced WAT differentiation and induced BAT differentiation in obese mice. GRIM19-transgenic mice exhibited reduced mitochondrial superoxide levels and a reciprocal balance between Th17 and Treg cells. These results suggest that GRIM19 attenuates the progression of obesity by controlling adipocyte differentiation. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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20 pages, 3494 KiB

Open AccessArticle

IL-6 Is Not Absolutely Essential for the Development of a TH17 Immune Response after an Aerosol Infection with Mycobacterium tuberculosis H37rv

by Kristina Ritter, Jan Christian Sodenkamp, Alexandra Hölscher, Jochen Behrends and Christoph Hölscher

Cells 2021, 10(1), 9; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010009 - 22 Dec 2020

Cited by 10 | Viewed by 2814

Abstract

Anti-inflammatory treatment of chronic inflammatory diseases often increases susceptibility to infectious diseases such as tuberculosis (TB). Since numerous chronic inflammatory and autoimmune diseases are mediated by interleukin (IL)-6-induced T helper (TH) 17 cells, a TH17-directed anti-inflammatory therapy may be preferable to an IL-12-dependent TH1 inhibition in order to avoid reactivation of latent infections. To assess, however, the risk of inhibition of IL-6-dependent TH17-mediated inflammation, we examined the TH17 immune response and the course of experimental TB in IL-6- and T-cell-specific gp130-deficient mice. Our study revealed that the absence of IL-6 or gp130 on T cells has only a minor effect on the development of antigen-specific TH1 and TH17 cells. Importantly, these gene-deficient mice were as capable as wild type mice to control mycobacterial infection. Together, in contrast to its key function for TH17 development in other inflammatory diseases, IL-6 plays an inferior role for the generation of TH17 immune responses during experimental TB. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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12 pages, 2042 KiB

Open AccessArticle

Early Treatment of Interleukin-33 can Attenuate Lupus Development in Young NZB/W F1 Mice

by Fatin Nurizzati Mohd Jaya, Zhongyi Liu and Godfrey Chi-Fung Chan

Cells 2020, 9(11), 2448; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112448 - 10 Nov 2020

Cited by 9 | Viewed by 2886

Abstract

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, has been recently associated with the development of autoimmune diseases, including systemic lupus erythematosus (SLE). IL-33 is an alarmin and a pleiotropic cytokine that affects various types of immune cells via binding to its receptor, ST2. In this study, we determine the impact of intraperitoneal IL-33 treatments in young lupus, NZB/W F1 mice. Mice were treated from the age of 6 to 11 weeks. We then assessed the proteinuria level, renal damage, survival rate, and anti-dsDNA antibodies. The induction of regulatory B (Breg) cells, changes in the level of autoantibodies, and gene expression were also examined. In comparison to the control group, young NZB/W F1 mice administered with IL-33 had a better survival rate as well as reduced proteinuria level and lupus nephritis. IL-33 treatments significantly increased the level of IgM anti-dsDNA antibodies, IL-10 expressing Breg cells, and alternatively-induced M2 macrophage gene signatures. These results imply that IL-33 exhibits a regulatory role during lupus onset via the expansion of protective IgM anti-dsDNA as well as regulatory cells such as Breg cells and M2 macrophages. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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14 pages, 2393 KiB

Open AccessArticle

Aberrant Bone Homeostasis in AML Is Associated with Activated Oncogenic FLT3-Dependent Cytokine Networks

by Isabel Bär, Volker Ast, Daria Meyer, Rainer König, Martina Rauner, Lorenz C. Hofbauer and Jörg P. Müller

Cells 2020, 9(11), 2443; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9112443 - 09 Nov 2020

Cited by 2 | Viewed by 2439

Abstract

Acute myeloid leukaemia (AML) is a haematopoietic malignancy caused by a combination of genetic and epigenetic lesions. Activation of the oncoprotein FLT3 ITD (Fms-like tyrosine kinase with internal tandem duplications) represents a key driver mutation in 25–30% of AML patients. FLT3 is a class III receptor tyrosine kinase, which plays a role in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Mutant FLT3 ITD results in an altered signalling quality, which causes cell transformation. Recent evidence indicates an effect of FLT3 ITD on bone homeostasis in addition to haematological aberrations. Using gene expression data repositories of FLT3 ITD-positive AML patients, we identified activated cytokine networks that affect the formation of the haematopoietic niche by controlling osteoclastogenesis and osteoblast functions. In addition, aberrant oncogenic FLT3 signalling of osteogenesis-specific cytokines affects survival of AML patients and may be used for prognosis. Thus, these data highlight the intimate crosstalk between leukaemic and osteogenic cells within the osteohaematopoietic niche. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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11 pages, 2278 KiB

Open AccessArticle

The Effects of Divalent Cation-Chelated Prion Fibrils on the Immune Response of EOC 13.31 Microglia Cells

by Huan-I Jen, Zih-You Lin, Jin-Xun Guo and Cheng-I Lee

Cells 2020, 9(10), 2285; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102285 - 13 Oct 2020

Cited by 5 | Viewed by 1921

Abstract

Transmissible spongiform encephalopathies (TSEs) are epidemic neurodegenerative diseases caused by prion proteins; in particular, they are induced by misfolded prion proteins (PrP^Sc). PrP^Sc tend to aggregate into insoluble amyloid prion fibrils (fPrP^WT), resulting in apoptosis of neuron cells and sequential neurodegeneration. Previous studies indicate that microglia cells play an important role in the innate immune system, and that these cells have good neuroprotection and delay the onset of TSEs. However, microglia can be a double-sided blade. For example, both Cu²⁺ and Mn²⁺ can induce microglia activation and secrete many inflammatory cytokines that are fatal to neuron cells. Unfortunately, PrP have cation binding sites at the N-terminus. When PrP^Sc accumulate during microglial phagocytosis, microglia may change the phenotype to secrete pro-inflammation cytokines, which increases the severity of the disease. Some studies have revealed an increase in the concentration of Mn²⁺ in the brains of patients. In this study, we treated microglia with fPrP^WT and cations and determined IκBα and IL-1β expression by Western blotting and quantitative polymerase chain reaction. The results showed that Mn–fPrP^WT decreased IκBα levels and dramatically increased IL-1β mRNA expression. In addition, competing binding between Cu²⁺ and Mn²⁺ can decrease the effect of Mn–fPrP^WT on IκBα and IL-1β. The effects of divalent cations and fPrP^WT in microglia inflammation are also discussed. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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16 pages, 2508 KiB

Open AccessArticle

Defining the CD39/CD73 Axis in SARS-CoV-2 Infection: The CD73^- Phenotype Identifies Polyfunctional Cytotoxic Lymphocytes

by Parimah Ahmadi, Philip Hartjen, Matin Kohsar, Silke Kummer, Stefan Schmiedel, Jan-Hendrik Bockmann, Anahita Fathi, Samuel Huber, Friedrich Haag and Julian Schulze zur Wiesch

Cells 2020, 9(8), 1750; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9081750 - 22 Jul 2020

Cited by 42 | Viewed by 5356

Abstract

The ectonucleotidases CD39 and CD73 regulate immune responses by balancing extracellular ATP and adenosine in inflammation and are likely to be involved in the pathophysiology of COVID-19. Here, we analyzed CD39 and CD73 on different lymphocyte populations in a small cohort of COVID-19 patients and in healthy individuals. We describe a significantly lower level of expression of CD73 on cytotoxic lymphocyte populations, including CD8⁺ T, natural killer T (NKT), and natural killer (NK) cells, during COVID-19. Interestingly, the decrease of CD73 on CD8⁺ T cells and NKT cells correlated with serum ferritin levels. Furthermore, we observed distinct functional differences between the CD73⁺ and CD73^- subsets of CD8⁺ T cells and NKT cells with regard to cytokine/toxin secretion. In COVID-19 patients, the majority of the CD73^-CD8⁺ T cells were capable of secreting granzyme B, perforin, tumor necrosis factor (TNF-α) or interferon-gamma (IFN-γ). To conclude, in this first study of CD39 and CD73 expression of lymphocytes in COVID-19, we show that CD8⁺ T cells and NKT cells lacking CD73 possess a significantly higher cytotoxic effector functionality compared to their CD73⁺ counterparts. Future studies should investigate differences of cellular CD39 and CD73 expression in patients at different disease stages and their potential as prognostic markers or targets for immunomodulatory therapies. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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18 pages, 7678 KiB

Open AccessArticle

Interleukin 26 Skews Macrophage Polarization Towards M1 Phenotype by Activating cJUN and the NF-κB Pathway

by Yi-Hsuan Lin, Yi-Hsun Wang, Yi-Jen Peng, Feng-Cheng Liu, Gu-Jiun Lin, Shing-Hwa Huang, Huey-Kang Sytwu and Chia-Pi Cheng

Cells 2020, 9(4), 938; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040938 - 10 Apr 2020

Cited by 34 | Viewed by 7876

Abstract

Interleukin 26 (IL-26) is a new member of the IL-10 family that is highly expressed in rheumatoid arthritis (RA). However, the functions of IL-26 produced by macrophages in RA have not been elucidated. In the present work, we evaluated the effects and the mechanisms of IL-26 on M1 and M2 macrophage differentiation. Human or mouse macrophage cells were treated with lipopolysaccharides (LPS), interferon gamma (IFNγ), or IL-4 alone or concurrently treated with IL-26 to monitor M1 or M2 macrophage subtypes. The expression level of M1 or M2 macrophage genes was evaluated by reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). The molecular mechanisms of downstream signaling activation during differentiation were investigated by immunoblotting assay. Our results found that IL-26 promoted macrophage cells from CD80⁺ M1 macrophage differentiation, not from the CD206⁺ M2 phenotype. The messenger RNA of M1-type macrophage markers tumor necrosis factor alpha (TNFα) and inducible nitric oxide synthase (iNOS) was up-regulated in the IL-26-treated group. Also, the M1-related proinflammatory cytokines TNFα and IL-6 were induced after IL-26 stimulation. Interestingly, IL-10, a cytokine marker of M2 macrophage, was also elevated after IL-26 stimulation. Moreover, the M1-like macrophage stimulated by IL-26 underwent cJUN, nuclear factor kappa B (NF-κB), and signal transducer and activator of transcription 1 (STAT1) activation. Our findings suggested the role of IL-26 in synovial macrophages of active rheumatoid arthritis and provided a new insight into IL-26 as a candidate therapeutic target in rheumatoid arthritis. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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Review

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24 pages, 2186 KiB

Open AccessReview

Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut

by Mousumi Mahapatro, Lena Erkert and Christoph Becker

Cells 2021, 10(1), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10010111 - 09 Jan 2021

Cited by 65 | Viewed by 12839

Abstract

Cytokines are small proteins that are secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate and adaptive immune responses, thereby playing a central role in genetic, inflammatory, and infectious diseases of the gut. Both, immune cells and gut epithelial cells, play important roles in intestinal disease development. The epithelium is located in between the mucosal immune system and the gut microbiome. It not only establishes an efficient barrier against gut microbes, but it also signals information from the gut lumen and its composition to the immune cell compartment. Communication across the epithelial cell layer also occurs in the other direction. Intestinal epithelial cells respond to immune cell cytokines and their response influences and shapes the microbial community within the gut lumen. Thus, the epithelium should be seen as a translator or a moderator between the microbiota and the mucosal immune system. Proper communication across the epithelium seems to be a key to gut homeostasis. Indeed, current genome-wide association studies for intestinal disorders have identified several disease susceptibility loci, which map cytokine signatures and their related signaling genes. A thorough understanding of this tightly regulated cytokine signaling network is crucial. The main objective of this review was to shed light on how cytokines can orchestrate epithelial functions such as proliferation, cell death, permeability, microbe interaction, and barrier maintenance, thereby safeguarding host health. In addition, cytokine-mediated therapy for inflammation and cancer are discussed. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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28 pages, 1571 KiB

Open AccessReview

The Role of gp130 Cytokines in Tuberculosis

by Kristina Ritter, Jasmin Rousseau and Christoph Hölscher

Cells 2020, 9(12), 2695; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122695 - 15 Dec 2020

Cited by 10 | Viewed by 3743

Abstract

Protective immune responses to Mycobacterium tuberculosis (Mtb) infection substantially depend on a delicate balance within cytokine networks. Thus, immunosuppressive therapy by cytokine blockers, as successfully used in the management of various chronic inflammatory diseases, is often connected with an increased risk for tuberculosis (TB) reactivation. Hence, identification of alternative therapeutics which allow the treatment of inflammatory diseases without compromising anti-mycobacterial immunity remains an important issue. On the other hand, in the context of novel therapeutic approaches for the management of TB, host-directed adjunct therapies, which combine administration of antibiotics with immunomodulatory drugs, play an increasingly important role, particularly to reduce the duration of treatment. In both respects, cytokines/cytokine receptors related to the common receptor subunit gp130 may serve as promising target candidates. Within the gp130 cytokine family, interleukin (IL)-6, IL-11 and IL-27 are most explored in the context of TB. This review summarizes the differential roles of these cytokines in protection and immunopathology during Mtb infection and discusses potential therapeutic implementations with respect to the aforementioned approaches. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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19 pages, 1049 KiB

Open AccessReview

Microbiota-Dependent Effects of IL-22

by Morsal Sabihi, Marius Böttcher, Penelope Pelczar and Samuel Huber

Cells 2020, 9(10), 2205; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102205 - 29 Sep 2020

Cited by 25 | Viewed by 4860

Abstract

Cytokines are important contributors to immune responses against microbial and environmental threats and are of particular importance at epithelial barriers. These interfaces are continuously exposed to external factors and thus require immune components to both protect the host from pathogen invasion and to regulate overt inflammation. Recently, substantial efforts have been devoted to understanding how cytokines act on certain cells at barrier sites, and why the dysregulation of immune responses may lead to pathogenesis. In particular, the cytokine IL-22 is involved in preserving an intact epithelium, maintaining a balanced microbiota and a functioning defense system against external threats. However, a tight regulation of IL-22 is generally needed, since uncontrolled IL-22 production can lead to the progression of autoimmunity and cancer. Our aim in this review is to summarize novel findings on IL-22 and its interactions with specific microbial stimuli, and subsequently, to understand their contributions to the function of IL-22 and the clinical outcome. We particularly focus on understanding the detrimental effects of dysregulated control of IL-22 in certain disease contexts. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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24 pages, 3342 KiB

Open AccessReview

IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions

by Doreen M. Floss, Jens M. Moll and Jürgen Scheller

Cells 2020, 9(10), 2184; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9102184 - 28 Sep 2020

Cited by 35 | Viewed by 6364

Abstract

Cytokines of the IL-12 family show structural similarities but have distinct functions in the immune system. Prominent members of this cytokine family are the pro-inflammatory cytokines IL-12 and IL-23. These two cytokines share cytokine subunits and receptor chains but have different functions in autoimmune diseases, cancer and infections. Accordingly, structural knowledge about receptor complex formation is essential for the development of new therapeutic strategies preventing and/or inhibiting cytokine:receptor interaction. In addition, intracellular signaling cascades can be targeted to inhibit cytokine-mediated effects. Single nucleotide polymorphisms can lead to alteration in the amino acid sequence and thereby influencing protein functions or protein–protein interactions. To understand the biology of IL-12 and IL-23 and to establish efficient targeting strategies structural knowledge about cytokines and respective receptors is crucial. A highly efficient therapy might be a combination of different drugs targeting extracellular cytokine:receptor assembly and intracellular signaling pathways. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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32 pages, 2406 KiB

Open AccessReview

Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

by Gloria Pastor-Fernández, Isabel R. Mariblanca and María N. Navarro

Cells 2020, 9(9), 2044; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9092044 - 07 Sep 2020

Cited by 38 | Viewed by 12842

Abstract

The interleukin 23 (IL-23) is a key pro-inflammatory cytokine in the development of chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases, multiple sclerosis, or rheumatoid arthritis. The pathological consequences of excessive IL-23 signaling have been linked to its ability to promote the production of inflammatory mediators, such as IL-17, IL-22, granulocyte-macrophage colony-stimulating (GM-CSF), or the tumor necrosis factor (TNFα) by target populations, mainly Th17 and IL-17-secreting TCRγδ cells (Tγδ17). Due to their pivotal role in inflammatory diseases, IL-23 and its downstream effector molecules have emerged as attractive therapeutic targets, leading to the development of neutralizing antibodies against IL-23 and IL-17 that have shown efficacy in different inflammatory diseases. Despite the success of monoclonal antibodies, there are patients that show no response or partial response to these treatments. Thus, effective therapies for inflammatory diseases may require the combination of multiple immune-modulatory drugs to prevent disease progression and to improve quality of life. Alternative strategies aimed at inhibiting intracellular signaling cascades using small molecule inhibitors or interfering peptides have not been fully exploited in the context of IL-23-mediated diseases. In this review, we discuss the current knowledge about proximal signaling events triggered by IL-23 upon binding to its membrane receptor to bring to the spotlight new opportunities for therapeutic intervention in IL-23-mediated pathologies. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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21 pages, 1935 KiB

Open AccessReview

The Roles of Endoplasmic Reticulum in NLRP3 Inflammasome Activation

by Yang Zhou, Zhizi Tong, Songhong Jiang, Wenyan Zheng, Jianjun Zhao and Xiangmei Zhou

Cells 2020, 9(5), 1219; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9051219 - 14 May 2020

Cited by 64 | Viewed by 8123

Abstract

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER–mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca²⁺ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Immunity)

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