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Inflammation in Chronic Disease: Molecular Mechanisms and Signaling Pathways
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Inflammation in Chronic Disease: Molecular Mechanisms and Signaling Pathways

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: 20 July 2025 | Viewed by 7812

Special Issue Editor

Dr. Nadia Lampiasi

E-Mail Website
Guest Editor
Istituto per la Ricerca e l’Innovazione Biomedica (IRIB), Consiglio Nazionale delle Ricereche (CNR), 00185 Rome, Italy
Interests: inflammation; innate immunity; macrophages; mast cells; osteoimmunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Inflammation is a physiological response of the body to various insults, such as pathogens, injuries, toxic compounds, and irradiation. The goal of inflammation is to remove harmful stimuli and damaged cells, and to initiate the healing process to restore tissue homeostasis. It is, therefore, a defense mechanism involving cells of the innate and adaptive immune system, molecules, cytokines, and cellular signals. However, sometimes the stimuli or damaged cells are not removed efficiently and, thus, the inflammation degenerates and becomes chronic, which can contribute to the development of many diseases, including autoimmune diseases, cancer, and nerve disorders. Much progress has been made recently and many molecular mechanisms, cytokines, and pathways involved are now known. By way of example: histamine, prostaglandins, platelet activating factors, leukotrienes, cytokines, oxidative stress, and transcription factors, such as NF-kB, MAPKs signaling, and the JAK-STAT pathway. The role of these components continues to be studied to better define the underlying scenario and the cells involved in inflammation to identify new therapeutic targets that will change the face of medicine in the near future. This Special Issue aims to collect publications on the current understanding of the molecular basis of inflammation and possible therapeutic targets to prevent the development of diseases associated with inflammation.

Dr. Nadia Lampiasi
Guest Editor

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Keywords

  • inflammation
  • neuroinflammation
  • immune response
  • inflammation-associated disease
  • inflammation mediators (proteins, enzymes, ecc)
  • cytokines
  • macrophages
  • mast cells
  • monocytes
  • dendritic cells
  • oxidative stress
  • signaling pathways

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Published Papers (4 papers)

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Research

16 pages, 2776 KiB  
Article
Agomelatine Mitigates Kidney Damage in Obese Insulin-Resistant Rats by Inhibiting Inflammation and Necroptosis via the TNF-α/NF-ĸB/p-RIPK3 Pathway
by Sasivimon Promsan, Nattavadee Pengrattanachot, Nichakorn Phengpol, Prempree Sutthasupha, La-ongdao Thongnak, Krit Jaikumkao and Anusorn Lungkaphin
Int. J. Mol. Sci. 2025, 26(5), 1940; https://doi.org/10.3390/ijms26051940 - 24 Feb 2025
Viewed by 518
Abstract
Obesity is a risk factor for chronic kidney disease. The expansion of adipose tissues in obesity induces insulin resistance and low-grade systemic inflammation, promoting kidney damage. Our previous studies have demonstrated that agomelatine (AGOM) exerts renoprotective effects in experimental models of obesity and [...] Read more.
Obesity is a risk factor for chronic kidney disease. The expansion of adipose tissues in obesity induces insulin resistance and low-grade systemic inflammation, promoting kidney damage. Our previous studies have demonstrated that agomelatine (AGOM) exerts renoprotective effects in experimental models of obesity and insulin resistance through various mechanisms, including the attenuation of ER stress and oxidative stress. This study aimed to further explore the effects of agomelatine on renal inflammation, insulin signaling, and necroptosis in obese, insulin-resistant rats. Obesity was induced in rats with a high-fat diet for 16 weeks, followed by 4 weeks of treatment with 20 mg kg−1 day−1 of AGOM or 10 mg kg−1 day−1 of pioglitazone (PIO). The results showed that insulin resistance was improved after treatment with AGOM and PIO, as demonstrated by the reduction in fasting plasma glucose, insulin, and HOMA-IR. Both treatments restored the levels of renal insulin signaling proteins. Moreover, AGOM inhibited TNFα, TNFR1, NF-ĸB, COX2, and IL1β, which attenuated the necroptosis-related proteins RIPK3 and MLKL. AGOM also prevented kidney DNA fragmentation, as detected by the TUNEL assay. In an obese condition, the level of the tight junction protein claudin-1 (CLDN1) was enhanced after being treated with AGOM. In conclusion, the novel mechanisms associated with AGOM and involved in limiting kidney injury were the inhibition of the TNFα/NF-ĸB/p-RIPK3 pathway and a reduction in inflammation and necroptosis. This suggested that AGOM could be an effective treatment for inhibiting kidney dysfunction in cases of obesity and insulin resistance. These findings open new avenues for the management of renal dysfunction, with implications for personalized medicine. Full article
(This article belongs to the Special Issue Inflammation in Chronic Disease: Molecular Mechanisms and Signaling Pathways)
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16 pages, 1955 KiB  
Article
Upregulation of Notch Signaling and Cell-Differentiation Inhibitory Transcription Factors in Stable Chronic Obstructive Pulmonary Disease Patients
by Antonino Di Stefano, Isabella Gnemmi, Umberto Rosani, Mauro Maniscalco, Silvestro Ennio D’Anna, Paola Brun, Vitina Carriero, Francesca Bertolini, Bruno Balbi and Fabio Luigi Massimo Ricciardolo
Int. J. Mol. Sci. 2024, 25(6), 3287; https://doi.org/10.3390/ijms25063287 - 14 Mar 2024
Cited by 2 | Viewed by 1558
Abstract
Notch signaling is involved in the prevention of cell differentiation and cell fate in various organs, including the lungs. We aimed to determine the transcriptomic and protein expression of Notch receptors, their ligands, and related transcription factors in stable COPD. The expression and [...] Read more.
Notch signaling is involved in the prevention of cell differentiation and cell fate in various organs, including the lungs. We aimed to determine the transcriptomic and protein expression of Notch receptors, their ligands, and related transcription factors in stable COPD. The expression and localization of Notch receptors, their ligands, and related transcription factors were measured in bronchial biopsies of individuals with stable mild/moderate (MCOPD) (n = 18) or severe/very severe (SCOPD) (n = 16) COPD, control smokers (CSs) (n = 13), and control nonsmokers (CNSs) (n = 11), and in the lung parenchyma of those with MCOPD (n = 13), CSs (n = 10), and CNSs (n = 10) using immunohistochemistry, ELISA tests, and transcriptome analyses. In the bronchial biopsies, Notch4 and HES7 significantly increased in the lamina propria of those with SCOPD compared to those with MCOPD, CSs, and CNSs. In the peripheral lung bronchiolar epithelium, Notch1 significantly increased in those with MCOPD and CSs compared to CNSs. ELISA tests of lung parenchyma homogenates showed significantly increased Notch2 in those with MCOPD compared to CSs and CNSs. Transcriptomic data in lung parenchyma showed increased DLL4 and HES1 mRNA levels in those with MCOPD and CSs compared to CNSs. These data show the increased expression of the Notch pathway in the lungs of those with stable COPD. These alterations may play a role in impairing the regenerative–reparative responses of diseased bronchioles and lung parenchyma. Full article
(This article belongs to the Special Issue Inflammation in Chronic Disease: Molecular Mechanisms and Signaling Pathways)
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22 pages, 6061 KiB  
Article
Thrombin-Induced COX-2 Expression and PGE2 Synthesis in Human Tracheal Smooth Muscle Cells: Role of PKCδ/Pyk2-Dependent AP-1 Pathway Modulation
by Chien-Chung Yang, I-Ta Lee, Yan-Jyun Lin, Wen-Bin Wu, Li-Der Hsiao and Chuen-Mao Yang
Int. J. Mol. Sci. 2023, 24(20), 15130; https://doi.org/10.3390/ijms242015130 - 13 Oct 2023
Cited by 3 | Viewed by 1668
Abstract
In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE2 in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated [...] Read more.
In this study, we confirmed that thrombin significantly increases the production of COX-2 and PGE2 in human tracheal smooth muscle cells (HTSMCs), leading to inflammation in the airways and lungs. These molecules are well-known contributors to various inflammatory diseases. Here, we investigated in detail the involved signaling pathways using specific inhibitors and small interfering RNAs (siRNAs). Our results demonstrated that inhibitors targeting proteins such as protein kinase C (PKC)δ, proline-rich tyrosine kinase 2 (Pyk2), c-Src, epidermal growth factor receptor (EGFR), phosphatidylinositol 3-kinase (PI3K), or activator protein-1 (AP-1) effectively reduced thrombin-induced COX-2 and PGE2 production. Additionally, transfection with siRNAs against PKCδ, Pyk2, c-Src, EGFR, protein kinase B (Akt), or c-Jun mitigated these responses. Furthermore, our observations revealed that thrombin stimulated the phosphorylation of key components of the signaling cascade, including PKCδ, Pyk2, c-Src, EGFR, Akt, and c-Jun. Thrombin activated COX-2 promoter activity through AP-1 activation, a process that was disrupted by a point-mutated AP-1 site within the COX-2 promoter. Finally, resveratrol (one of the most researched natural polyphenols) was found to effectively inhibit thrombin-induced COX-2 expression and PGE2 release in HTSMCs through blocking the activation of Pyk2, c-Src, EGFR, Akt, and c-Jun. In summary, our findings demonstrate that thrombin-induced COX-2 and PGE2 generation involves a PKCδ/Pyk2/c-Src/EGFR/PI3K/Akt-dependent AP-1 activation pathway. This study also suggests the potential use of resveratrol as an intervention for managing airway inflammation. Full article
(This article belongs to the Special Issue Inflammation in Chronic Disease: Molecular Mechanisms and Signaling Pathways)
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14 pages, 1654 KiB  
Article
High-Intensity Interval Training Ameliorates High-Fat Diet-Induced Metabolic Disorders via the Cyclic GMP-AMP Synthase-Stimulator of Interferon Gene Signaling Pathway
by Zhiwen Hu, Xi Li, Yangjun Yang, Zhe Zhang and Shuzhe Ding
Int. J. Mol. Sci. 2023, 24(18), 13840; https://doi.org/10.3390/ijms241813840 - 8 Sep 2023
Viewed by 2216
Abstract
Metabolic diseases are growing in prevalence worldwide. Although the pathogenesis of metabolic diseases remains ambiguous, the correlation between cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) and metabolic diseases has been identified recently. Exercise is an effective intervention protecting against metabolic diseases, however, [...] Read more.
Metabolic diseases are growing in prevalence worldwide. Although the pathogenesis of metabolic diseases remains ambiguous, the correlation between cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) and metabolic diseases has been identified recently. Exercise is an effective intervention protecting against metabolic diseases, however, the role of the cGAS-STING signaling pathway in this process is unclear, and the effect and mechanism of different exercise intensities on metabolic disorders are still unknown. Thus, we explored the association between exercise to ameliorate HFD-induced metabolic disorders and the cGAS-STING signaling pathway and compared the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). Male C57BL/6 mice (6–8 weeks old) were fed HFD for 8 weeks to establish a metabolic disease model and were subjected to 8-week MICT or HIIT training. Glucose tolerance tests (GTT) and insulin tolerance tests (ITT) were used to assess glucose metabolism. Serum triglyceride (TG) and total cholesterol (TC) were measured to evaluate lipid metabolism. Oil red staining was used to observe the lipid droplets in the gastrocnemius muscle. An enzyme-linked immunosorbent assay was used to detect the serum inflammatory factors IL-6 and IFN-β. The protein expression of the cGAS-STING signaling pathway was detected by the WesTM automatic protein expression analysis system. We reported that HFD induced metabolic disorders with obesity, abnormal glucolipid metabolism, and significant inflammatory responses. Both HIIT and MICT ameliorated the above adverse reactions, but MICT was superior to HIIT in improving glucolipid disorders. Additionally, HIIT significantly increased the expression of STING protein, as well as the phosphorylation of TBKI and the ratio of p-IRF3/IRF3. MICT only increased the expression of STING protein. Our findings suggest that HIIT may alleviate HFD-induced metabolic disorder phenotype through the cGAS-STING signaling pathway. However, the improvement of MICT on metabolic disorder phenotype is less associated with the cGAS-STING pathway, which needs to be further explored. Full article
(This article belongs to the Special Issue Inflammation in Chronic Disease: Molecular Mechanisms and Signaling Pathways)
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