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Immune Regulation in Lung Diseases

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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 (25 February 2026) | Viewed by 5098

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Special Issue Editors

Dr. Chiara Colarusso

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Guest Editor

Department of Pharmacy, University of Salerno, Salerno, Italy
Interests: inflammasome; immunology; lung cancer
Special Issues, Collections and Topics in MDPI journals

Dr. Rosalinda Sorrentino

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Guest Editor

Department of Pharmacy (DIFARMA), University of Salerno, Salerno, Italy
Interests: immunotherapy and target therapy; cancer; inflammation; immunity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The lung is constantly exposed to a plethora of threats, which can induce infection, inflammation or tissue injury, paving the way for the establishment of lung diseases, such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma and, even worse, cancer. Under physiological conditions, the airways are protected against pathogens and irritants by innate and adaptive immunity cells, which in association with structural cells orchestrate lung immunity to minimize lung disease and ensure a balanced response, thus avoiding excessive inflammatory reactions and subsequent lung tissue damage. Thus, the key role of immune regulation in either the resolution or establishment of lung disease appears clear. In this context, the intercellular communication between the epithelial and immune cells is facilitated by lipid mediators, cytokines and chemokines, which in turn promote the attraction of various immune cellular populations to shape lung microenvironment. In this context, a better understanding of the complexity and dynamicity of the lung immune system, especially through multi-omics and computational approaches, is pivotal in order to determine how respiratory immunity interacts with other complex networks in pathological conditions and to provide a basis for the selection of novel therapeutic strategies against lung diseases. Overall, the elucidation of immune regulation in lung disease could contribute to the development of tailored interventions for optimizing therapeutic outcomes in respiratory disease management.

Dr. Chiara Colarusso
Dr. Rosalinda Sorrentino
Guest Editors

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Keywords

lung disease
immune system
lung immune cells
lung epithelial cells
therapy

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Published Papers (5 papers)

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Research

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43 pages, 3005 KB

Open AccessArticle

Integrative Vitamin D-Inflammatory-Coagulation Biomarker Index Predicts COVID-19 Severity: Development and Validation of the Vitamin D Inflammatory Burden Score (VDIBS)

by Joško Osredkar, Uroš Godnov and Darko Siuka

Int. J. Mol. Sci. 2026, 27(4), 1770; https://doi.org/10.3390/ijms27041770 - 12 Feb 2026

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Abstract

Vitamin D deficiency is common in hospitalized COVID-19 patients and is associated with increased severity. However, single-biomarker approaches provide insufficient prognostic precision. We developed an integrative inflammatory-metabolic risk index combining vitamin D status, systemic inflammation, and coagulation activation. This is a prospective cohort study of 512 hospitalized COVID-19 patients (September 2022–December 2023) with serum 25(OH)D3 measurement at admission. The primary analysis (N = 301) included patients with complete data for VDIBS-Core components (CRP, ferritin, D-dimer, LDH). The Vitamin D Inflammatory Burden Score-Core (VDIBS-Core; range 0–7) integrated the following: (1) vitamin D tier (deficient < 30 nmol/L: 3 points; insufficient 30–50: 2; non-optimal 50–75: 1; sufficient > 75: 0), (2) inflammation score (CRP ≥ 100, ferritin ≥ 1000 each +1 point; 0–2 total), and (3) coagulation score (D-dimer ≥ 1000, LDH ≥ 3–6 or ≥ 6 each +0–2 points; 0–2 total). The IL-6 measurement (N = 48, 9.4%) was explored separately as VDIBS-Plus in the secondary analysis. The outcomes were severe COVID-19 (defined as the worst severity classification during hospitalization per WHO criteria), ICU admission, and mortality. The mean vitamin D was 63.4 ± 33.2 nmol/L (68.1% deficient). Among N = 301 with complete VDIBS-Core data, severe disease occurred in 221 (73.4%), ICU admission in 15 (5.0%), and mortality in 8 (2.7%). VDIBS-Core risk stratification showed the following: low-risk (VDIBS 0–2, n = 178) 8.4% severe; moderate-risk (VDIBS 3–5, n = 245) 45.7% severe; and high-risk (VDIBS 6–7, n = 89) 78.6% severe; χ² = 142.3, p < 0.001. VDIBS-Core predicted severe disease with AUC 0.78 (95% CI 0.74–0.82), with excellent calibration (Hosmer–Lemeshow p = 0.40). When compared to complex multivariate models incorporating all seven individual biomarkers, VDIBS-Core demonstrated equivalent discrimination (AUC 0.82, Δ = 0.04, p = 0.08, not statistically significant) with superior clinical simplicity. Bootstrap internal validation confirmed modest optimism (optimism-corrected AUC 0.76). An incremental value analysis demonstrated that the vitamin D component contributes a significant additional predictive value compared to inflammation/coagulation biomarkers alone (LR test p = 0.004). VDIBS-Core provides bedside-implementable risk stratification using three simple components measurable in <5 min, integrating vitamin D-dependent immune regulation with systemic inflammation and coagulation activation. This composite approach offers a practical tool for treatment intensity escalation and monitoring frequency assignment in hospitalized COVID-19 patients. External validation in geographically diverse cohorts is required before widespread clinical implementation. Full article

(This article belongs to the Special Issue Immune Regulation in Lung Diseases)

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13 pages, 1161 KB

Open AccessArticle

Role of Myeloid Cell Glucose Transporter 1 in the Host Response During Pneumonia Caused by Streptococcus pneumoniae

by Liza Pereverzeva, Valentine Léopold, Anno Saris, Alex R. Schuurman, Joe M. Butler, Tom D. Y. Reijnders, Joris J. T. H. Roelofs, Daniël R. Faber, W. Joost Wiersinga, Cornelis van’t Veer, Alex F. de Vos and Tom van der Poll

Int. J. Mol. Sci. 2025, 26(21), 10461; https://doi.org/10.3390/ijms262110461 - 28 Oct 2025

Viewed by 903

Abstract

During infection, myeloid cells are subjected to a fast increase in energy demand. Glucose transporter 1 (GLUT1) is a key mediator of glucose metabolism, especially for glycolysis. The present study aimed to investigate GLUT1 expression in monocytes and neutrophils from patients with community-acquired pneumonia (CAP) and to determine the functional role of GLUT1 in the responsiveness during pneumonia evoked in mice by Streptococcus (S.) pneumoniae, the most common causative pathogen in CAP. GLUT1 expression in monocytes and neutrophils of patients and controls was determined by RNA sequencing and flow cytometry analysis. Myeloid cell-specific GLUT1-deficient mice and controls were intranasally infected with S. pneumoniae, after which bacterial loads, lung pathology, and cytokine levels were analyzed. GLUT1 gene expression was upregulated in monocytes from CAP patients in comparison to matched subjects without infection, and protein expression was increased upon ex vivo activation. In neutrophils, GLUT1 mRNA levels were significantly upregulated in CAP patients, but protein levels were not altered. Surprisingly, myeloid-specific GLUT1-deficient mice displayed an unaltered host response during pneumococcal pneumonia. These data suggest that GLUT1 may contribute to immune responses of myeloid cells during CAP, but that its role may be superseded by other mechanisms during pneumococcal pneumonia. Full article

(This article belongs to the Special Issue Immune Regulation in Lung Diseases)

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14 pages, 1655 KB

Open AccessArticle

Evaluating the Dose-Dependent Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells in a Preclinical Model of Interstitial Lung Disease

by Takuya Kotani, Takashi Saito, Ryota Masutani, Satsuki Uemura, Shogo Matsuda, Takayasu Suzuka, Masaki Ikemoto and Tohru Takeuchi

Int. J. Mol. Sci. 2025, 26(20), 10016; https://doi.org/10.3390/ijms262010016 - 15 Oct 2025

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Abstract

Interstitial lung disease associated with connective tissue disease (CTD-ILD) is a severe condition characterized by inflammation and progressive lung fibrosis, with limited treatment options. Previous studies have demonstrated the anti-inflammatory and antifibrotic properties of human umbilical cord-derived mesenchymal stem cells (huMSCs), suggesting their potential as novel therapeutic agents. Therefore, we investigated the dose-dependent therapeutic effects of huMSCs on CTD-ILD. A bleomycin-induced mouse model of interstitial lung disease, in which female C57BL/6J mice developed diffuse pulmonary lesions following continuous subcutaneous infusion of bleomycin, was used. Mice subsequently received intravenous huMSCs at doses of 1.0 × 10³, 1.0 × 10⁴, or 1.0 × 10⁵ cells. The medium dose (1.0 × 10⁴ cells) showed the most pronounced effects on pulmonary fibrosis and collagen deposition, while significantly suppressing pro-inflammatory cytokines, including interleukin-1β and interleukin-6; however, this effect was not consistent across all measured outcomes. The treatment also enhanced beneficial matrix remodeling by downregulating TIMP-1 and upregulating MMP-9 expression. Furthermore, huMSC administration modulated macrophage polarization and inhibited the pro-inflammatory M1 phenotype. These findings highlight the therapeutic potential of huMSCs for CTD-ILD and underscore the importance of dose optimization to balance efficacy and safety. Full article

(This article belongs to the Special Issue Immune Regulation in Lung Diseases)

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14 pages, 729 KB

Open AccessArticle

Role of the Inflammasome Pathway According to the Expression of Proteins and Genetic Polymorphisms in COVID-19 Patients

by Thiago Rodrigues dos Santos, Lucas Baena Carstens, Leonardo Vinícius Barbosa, Mariana Collete, Natan de Araujo, Caroline Busatta Vaz de Paula, Marina Luise Viola Azevedo, Ana Clara de Almeida, Seigo Nagashima, Lucia de Noronha and Cleber Machado-Souza

Int. J. Mol. Sci. 2025, 26(20), 9993; https://doi.org/10.3390/ijms26209993 - 14 Oct 2025

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Abstract

COVID-19 severity is frequently linked to exacerbated inflammation, with the inflammasome pathway playing a key role in activating inflammatory interleukins. This observational post-mortem study evaluated the expression of inflammasome-associated molecules in patients who died from COVID-19 during the second wave. Minimally invasive autopsies were performed on patients from the first (n = 24) and second (n = 18) waves. Lung tissue samples underwent immunohistochemical staining for ACE-2, TLR-4, NF-κB, TNF-α, NOX4, NLRP3, ASC, CASPASE-1, IL-1β, IL-18, GSDMD, and CASPASE-9. Additionally, genetic polymorphisms within inflammasome-related genes were assessed via real-time polymerase chain reaction. Lung tissue expressions of TLR-4, NLRP3, and IL-18 were significantly higher in patients from the second wave compared to those from the first, with expression levels of 26.3 versus 12.1, 13.9 versus 6.4, and 25.6 versus 3.8, respectively. The A allele at rs4648090 of NFKB1 and the T allele at rs317155 of NOX4 were associated with increased corresponding protein expression by factors of 5.1 and 8.9, respectively. Notably, IL-18 demonstrated substantial immunological relevance, correlating strongly with elevated expression linked to these genetic variants in second wave cases. These findings suggest that the inflammasome pathway harbors biologically meaningful molecules implicated in severe COVID-19, meriting further investigation for their potential as diagnostic or therapeutic targets. Full article

(This article belongs to the Special Issue Immune Regulation in Lung Diseases)

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Review

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21 pages, 714 KB

Open AccessReview

Metabolic Checkpoints and Lymphoid Neogenesis in Lung Dendritic Cells: Mechanisms Guiding Tolerance and Chronic Lung Inflammation

by Dara C. Fonseca-Balladares, Gabriela O. S. Costa, Kevin Nolan, Michael H. Lee, Thaís C. F. Menezes, Brian B. Graham and Claudia Mickael

Int. J. Mol. Sci. 2026, 27(6), 2887; https://doi.org/10.3390/ijms27062887 - 23 Mar 2026

Viewed by 771

Abstract

Dendritic cells (DCs) are key sentinels in the lung mucosa that interpret environmental signals to either promote tolerance or trigger inflammation, influencing the development of chronic lung diseases. This review highlights recent mechanistic insights showing that metabolic checkpoints serve as upstream regulators of DC fate and activity: inflammatory stimuli activate HIF-1α/mTOR-linked glycolytic pathways that drive maturation, cytokine secretion, antigen presentation, and migration. In contrast, AMPK-related oxidative and lipid metabolism pathways support tolerogenic states that encourage regulatory T-cell responses and inhibit checkpoints like PD-1/PD-L1. We also present evidence that DC subset specialization (cDC1 vs. cDC2) and their tissue location interact with these metabolic pathways to regulate lymphoid tissue formation, including the development and persistence of tertiary lymphoid structures in chronically inflamed lungs. These ectopic lymphoid tissues enhance local immune responses through DC–stromal interactions and ongoing T follicular helper–B cell communication, contributing to persistent inflammation and tissue remodeling in conditions such as COPD, asthma, pulmonary hypertension, and fibrotic interstitial lung disease. Finally, we discuss the translational potential of targeting this immunometabolic–lymphoid pathway, suggesting that modulating metabolic regulators, migratory circuits, and tolerogenic programs could restore immune balance while maintaining host defense—a promising framework for developing advanced therapies for chronic lung inflammation. Full article

(This article belongs to the Special Issue Immune Regulation in Lung Diseases)

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