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Roles of Inflammasomes in Inflammatory Responses and Human Diseases
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Roles of Inflammasomes in Inflammatory Responses and Human Diseases

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (20 April 2025) | Viewed by 8567

Special Issue Editor

Dr. Young-Su Yi

E-Mail Website
Guest Editor
Department of Life Sciences, Kyonggi University, Suwon 16227, Republic of Korea
Interests: inflammation; inflammatory/autoimmune diseases; non-canonical inflammasomes; macrophage; anti-inflammatory therapeutics, signaling transduction; immunology; molecular biology; biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inflammation is an innate immune defense that protects our body tissues from pathogens and cellular dangers; however, repeated and prolonged inflammation known as chronic inflammation has been considered as a key risk factor for a variety of human diseases, including inflammatory, autoimmune, infectious diseases, and even cancers. An inflammatory response is initiated when the pathogen recognition receptors (PRRs) of the inflammatory cells recognize the pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs), which results in the activation of multiple inflammatory signaling pathways. An inflammatory response consists of two successive steps, priming and triggering. Priming is the step to prepare inflammatory responses by upregulating inflammatory genes, while triggering is the step to activate and boost inflammatory responses by activating inflammasomes and intracellular multiprotein complexes responsible for the stimulation of inflammatory responses. Therefore, inflammasome activation has been regarded as a key determinant for the induction of inflammatory responses and the progression of various human diseases, and the inhibition of inflammatory responses by selective targeting of inflammasomes has been suggested as a promising strategy to develop novel therapeutics for the treatment of these human diseases. However, the roles of inflammasomes and their dysregulation during inflammatory responses and human diseases are still largely unknown and remain to be investigated.

This Special Issue welcomes studies exploring but not limited to the “Roles of Inflammasomes in Inflammatory Responses and Human Diseases”, identifying and validating novel targets regulating inflammasome functions, evaluating anti-inflammatory effects by targeting inflammasomes, and developing potential inflammasome-targeted therapeutics.

Dr. Young-Su Yi
Guest Editor

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Keywords

  • inflammasome
  • inflammatory responses
  • human diseases
  • anti-inflammatory therapeutics

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Related Special Issue

Published Papers (6 papers)

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Research

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16 pages, 2970 KiB  
Article
PDE10A Inhibition Reduces NLRP3 Activation and Pyroptosis in Sepsis and Nerve Injury
by Bradford C. Berk, Camila Lage Chávez and Chia George Hsu
Int. J. Mol. Sci. 2025, 26(10), 4498; https://doi.org/10.3390/ijms26104498 - 8 May 2025
Viewed by 115
Abstract
Cell death and inflammation are key innate immune responses, but excessive activation can cause tissue damage. The NLRP3 inflammasome is a promising target for reducing inflammation and promoting recovery. Immunometabolism regulates NLRP3 responses in neurological and inflammatory diseases through cyclic nucleotide signaling. Targeting [...] Read more.
Cell death and inflammation are key innate immune responses, but excessive activation can cause tissue damage. The NLRP3 inflammasome is a promising target for reducing inflammation and promoting recovery. Immunometabolism regulates NLRP3 responses in neurological and inflammatory diseases through cyclic nucleotide signaling. Targeting phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, offer a novel approach to mitigate inflammation. While 14 PDE inhibitors are FDA-approved, PDE10A’s role in NLRP3 inflammasome activation remains unclear. This study investigates the effects of PDE10A inhibition on inflammasome-driven inflammation using two PDE10A inhibitors, MP-10 and TP-10, in macrophage and animal models of sepsis and traumatic nerve injury. Our results show that PDE10A inhibition reduces inflammasome activation by preventing ASC speck formation and by lowering levels of cleaved caspase-1, gasdermin D, and IL-1β, which are key mediators of pyroptosis. In the sepsis model, MP-10 significantly reduced inflammation, decreased plasma IL-1β, alleviated thrombocytopenia, and improved organ damage markers. In the nerve injury model, PDE10A inhibition enhanced motor function recovery and reduced muscle atrophy-related gene expression. These findings suggest that PDE10A inhibition could be a promising therapeutic approach for inflammatory and neuromuscular injuries. Given MP-10’s established safety in human trials, Phase 2 clinical studies for sepsis and nerve injury are highly promising. Full article
(This article belongs to the Special Issue Roles of Inflammasomes in Inflammatory Responses and Human Diseases)
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14 pages, 1811 KiB  
Article
COVID-19 Induces Greater NLRP3 Inflammasome Activation in Obese Patients than Other Chronic Illnesses: A Case–Control Study
by Raíssa Campos D’Amico, Seigo Nagashima, Lucas Baena Carstens, Karina de Guadalupe Bertoldi, Sabrina Mataruco, Júlio Cesar Honório D’Agostini, Elisa Carolina Hlatchuk, Sofia Brunoro da Silva, Lucia de Noronha and Cristina Pellegrino Baena
Int. J. Mol. Sci. 2025, 26(4), 1541; https://doi.org/10.3390/ijms26041541 - 12 Feb 2025
Viewed by 829
Abstract
Obesity has been identified as an independent risk factor for severe COVID-19 unfavorable outcomes. Several factors, such as increased ACE2 receptor expression and chronic inflammation, can contribute to this relationship, yet the activation of the NLRP3 inflammasome pathway is also a key element. [...] Read more.
Obesity has been identified as an independent risk factor for severe COVID-19 unfavorable outcomes. Several factors, such as increased ACE2 receptor expression and chronic inflammation, can contribute to this relationship, yet the activation of the NLRP3 inflammasome pathway is also a key element. Our primary goal was to determine whether chronic NLRP3 inflammasome activation in people with obesity is different in critical COVID-19 and in critical chronic conditions. A retrospective analysis was conducted using clinical data and post-mortem lung tissue samples from 14 COVID-19 patients with obesity (group A) and 9 patients with obesity who died from non-COVID-19 causes (group B). Immunohistochemical analysis assessed twelve markers related to the NLRP3 inflammasome pathway. Group A showed a significantly higher expression of ASC (p = 0.0387) and CASP-1 (p = 0.0142). No significant differences were found for IL-8, TNF-α, NF-kB, NLRP3, IL-1β, and gasdermin-D. Group B had higher levels of IL-6 (p < 0.0001), IL-18 (p = 0.002), CASP-9 (p < 0.0001), and HIF (p = 0.0327). We concluded that COVID-19 activates the NLRP3 inflammasome pathway, possibly leading to pyroptotic cell death mediated by caspase-1. In contrast, people with obesity without COVID-19, despite exhibiting some markers of the NLRP3 inflammasome, are more likely to experience necroptosis mediated by caspase-9. Full article
(This article belongs to the Special Issue Roles of Inflammasomes in Inflammatory Responses and Human Diseases)
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18 pages, 3295 KiB  
Article
DINCH Exposure Triggers Inflammatory, Oxidative, and Apoptotic Pathways in the Liver of Long-Evans Lactating Rats and Their Offspring
by Lucía Íñigo-Catalina, Beatriz Linillos-Pradillo, Margret Schlumpf, Walter Lichtensteiger, Sergio D. Paredes, Lisa Rancan and Jesús A. F. Tresguerres
Int. J. Mol. Sci. 2024, 25(23), 13017; https://doi.org/10.3390/ijms252313017 - 3 Dec 2024
Viewed by 1166
Abstract
1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) is a non-phthalate plasticizer used as a replacement of di(2-ethylhexyl) phthalate (DEHP) in daily usage items. It is not known whether continuous exposure to low doses of DINCH can lead to hepatic alterations, the liver being the [...] Read more.
1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) is a non-phthalate plasticizer used as a replacement of di(2-ethylhexyl) phthalate (DEHP) in daily usage items. It is not known whether continuous exposure to low doses of DINCH can lead to hepatic alterations, the liver being the organ responsible for its metabolism. The aim of this study was to evaluate the activation of inflammatory and apoptotic pathways in the liver of lactating dams after DINCH exposure, and whether these effects may be observed on postnatal day 6 (PND6) offspring. Two doses of DINCH were tested by oral administration to the following three groups of Long-Evans rats: control, DINCH-lower dose (LDINCH, 30 mg/kg b.w./day), and DINCH-high dose (HDINCH, 300 mg/kg b.w./day). Inflammatory mediators (IL-1β, TNF-α, NF-κB), mitochondrial transcriptional factors (PPARγ and PGC-1α), oxidative stress markers (SOD, CAT, GSSG/GSH), and components of the mitochondrial apoptotic pathway (PUMA, BAX, BAD, Bcl-2, Bcl-xL, Cytochrome c, APAF-1, Caspase-3, AIF) were assessed by the gene and protein expression in the liver of lactating dams and offspring. Exposure to LDINCH promoted the release of pro-inflammatory cytokines such as IL-1β and TNF-α and raised oxidative stress levels (GSSG/GSH), as well as increased Caspase-3 levels and reduced anti-apoptotic proteins (Bcl-2 and Bcl-xL), both in lactating dams and PND6 offspring. Thus, constant exposure to lower doses of DINCH can disrupt inflammatory and oxidant/antioxidant homeostasis, leading to hepatic tissue damage in lactating dams and having a perinatal effect in PND6 offspring. Full article
(This article belongs to the Special Issue Roles of Inflammasomes in Inflammatory Responses and Human Diseases)
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19 pages, 2687 KiB  
Article
Influence of Donor-Specific Characteristics on Cytokine Responses in H3N2 Influenza A Virus Infection: New Insights from an Ex Vivo Model
by Chung-Guei Huang, Ming-Ju Hsieh, Yi-Cheng Wu, Po-Wei Huang, Ya-Jhu Lin, Kuo-Chien Tsao, Shin-Ru Shih and Li-Ang Lee
Int. J. Mol. Sci. 2024, 25(20), 10941; https://doi.org/10.3390/ijms252010941 - 11 Oct 2024
Viewed by 1731
Abstract
Influenza A virus (IAV) is known for causing seasonal epidemics ranging from flu to more severe outcomes like pneumonia, cytokine storms, and acute respiratory distress syndrome. The innate immune response and inflammasome activation play pivotal roles in sensing, preventing, and clearing the infection, [...] Read more.
Influenza A virus (IAV) is known for causing seasonal epidemics ranging from flu to more severe outcomes like pneumonia, cytokine storms, and acute respiratory distress syndrome. The innate immune response and inflammasome activation play pivotal roles in sensing, preventing, and clearing the infection, as well as in the potential exacerbation of disease progression. This study examines the complex relationships between donor-specific characteristics and cytokine responses during H3N2 IAV infection using an ex vivo model. At 24 h post infection in 31 human lung explant tissue samples, key cytokines such as interleukin (IL)-6, IL-10, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ) were upregulated. Interestingly, a history of lung cancer did not impact the acute immune response. However, cigarette smoking and programmed death-ligand 1 (PD-L1) expression on macrophages significantly increased IL-2 levels. Conversely, age inversely affected IL-4 levels, and diabetes mellitus negatively influenced IL-6 levels. Additionally, both diabetes mellitus and programmed cell death protein 1 (PD-1) expression on CD3+/CD4+ T cells negatively impacted TNF-α levels, while body mass index was inversely associated with IFN-γ production. Toll-like receptor 2 (TLR2) expression emerged as crucial in mediating acute innate and adaptive immune responses. These findings highlight the intricate interplay between individual physiological traits and immune responses during influenza infection, underscoring the importance of tailored and personalized approaches in IAV treatment and prevention. Full article
(This article belongs to the Special Issue Roles of Inflammasomes in Inflammatory Responses and Human Diseases)
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16 pages, 1141 KiB  
Article
Weight Status, Autonomic Function, and Systemic Inflammation in Children with Obstructive Sleep Apnea
by Hai-Hua Chuang, Chung-Guei Huang, Jen-Fu Hsu, Li-Pang Chuang, Yu-Shu Huang, Hsueh-Yu Li and Li-Ang Lee
Int. J. Mol. Sci. 2024, 25(16), 8951; https://doi.org/10.3390/ijms25168951 - 16 Aug 2024
Cited by 2 | Viewed by 1228
Abstract
Children with obstructive sleep apnea (OSA) frequently experience chronic low-grade systemic inflammation, with the inflammasome playing a central role in OSA. This cross-sectional study evaluated the relationship between weight status, autonomic function, and systemic inflammation in a cohort of 55 children with OSA, [...] Read more.
Children with obstructive sleep apnea (OSA) frequently experience chronic low-grade systemic inflammation, with the inflammasome playing a central role in OSA. This cross-sectional study evaluated the relationship between weight status, autonomic function, and systemic inflammation in a cohort of 55 children with OSA, predominantly boys (78%) with an average age of 7.4 ± 2.2 years and an apnea-hypopnea index of 14.12 ± 17.05 events/hour. Measurements were taken of body mass index (BMI), sleep heart-rate variability, morning circulatory levels of interleukin-1β, interleukin-1 receptor antagonist, and interleukin-6, and tumor necrosis factor-α, anthropometry, and polysomnography. Multiple linear regression modeling showed that an apnea-hypopnea index was significantly associated with BMI, the standard deviation of successive differences between normal-to-normal intervals during N3 sleep, and the proportion of normal-to-normal interval pairs differing by more than 50 ms during rapid-eye-movement sleep. A moderated mediation model revealed that interleukin-1 receptor antagonist levels mediated the association between BMI and interleukin-6 levels, with sympathovagal balance during N3 sleep and minimum blood oxygen saturation further moderating these relationships. This study highlights the complex relationships between BMI, polysomnographic parameters, sleep heart-rate-variability metrics, and inflammatory markers in children with OSA, underlining the importance of weight management in this context. Full article
(This article belongs to the Special Issue Roles of Inflammasomes in Inflammatory Responses and Human Diseases)
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Review

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17 pages, 1959 KiB  
Review
Roles of the Caspase-11 Non-Canonical Inflammasome in Rheumatic Diseases
by Young-Su Yi
Int. J. Mol. Sci. 2024, 25(4), 2091; https://doi.org/10.3390/ijms25042091 - 8 Feb 2024
Cited by 6 | Viewed by 2611
Abstract
Inflammasomes are intracellular multiprotein complexes that activate inflammatory signaling pathways. Inflammasomes comprise two major classes: canonical inflammasomes, which were discovered first and are activated in response to a variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and non-canonical inflammasomes, which [...] Read more.
Inflammasomes are intracellular multiprotein complexes that activate inflammatory signaling pathways. Inflammasomes comprise two major classes: canonical inflammasomes, which were discovered first and are activated in response to a variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and non-canonical inflammasomes, which were discovered recently and are only activated in response to intracellular lipopolysaccharide (LPS). Although a larger number of studies have successfully demonstrated that canonical inflammasomes, particularly the NLRP3 inflammasome, play roles in various rheumatic diseases, including rheumatoid arthritis (RA), infectious arthritis (IR), gouty arthritis (GA), osteoarthritis (OA), systemic lupus erythematosus (SLE), psoriatic arthritis (PA), ankylosing spondylitis (AS), and Sjögren’s syndrome (SjS), the regulatory roles of non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 non-canonical inflammasomes, in these diseases are still largely unknown. Interestingly, an increasing number of studies have reported possible roles for non-canonical inflammasomes in the pathogenesis of various mouse models of rheumatic disease. This review comprehensively summarizes and discusses recent emerging studies demonstrating the regulatory roles of non-canonical inflammasomes, particularly focusing on the caspase-11 non-canonical inflammasome, in the pathogenesis and progression of various types of rheumatic diseases and provides new insights into strategies for developing potential therapeutics to prevent and treat rheumatic diseases as well as associated diseases by targeting non-canonical inflammasomes. Full article
(This article belongs to the Special Issue Roles of Inflammasomes in Inflammatory Responses and Human Diseases)
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