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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 (20 April 2023) | Viewed by 33320

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Special Issue Editors

Dr. Yi-Giien Tsai

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Guest Editor

1. Division of Pediatric Allergy and Immunology and Rheumatology, Changhua Christian Children’s Hospital, Changhua 50050, Taiwan
2. School of Medicine, Chung Shan Medical University, Taichung 40402, Taiwan
3. School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Interests: alveolar macrophages; innate immunity; oxidative stress; regulatory T cells, allergy; autoimmunity; immunotherapy

Dr. Chih-Hsing Hung

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Guest Editor

Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Interests: macrophage; dendritic cell; monocyte; asthma; ROS; mitophage; environmental hormone

Dr. Hung-Ming Wu

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Guest Editor

1. Department of Neurology, Changhua Christian Hospital, Changhua 50050, Taiwan
2. Graduate Institute of Acupuncture Science, China Medical University, Taichung 40402, Taiwan
Interests: macrophages; M1 microglia; M2 microglia; innate immunity; oxidative stress; systemic inflammation; neuroinflammation

Special Issue Information

Dear Colleagues,

Macrophages are heterogeneous and plastic, and their function is regulated by the surrounding microenvironment. Macrophages are key components of the innate immune system and are involved in the regulation of inflammation, repair, and regeneration. Many studies have documented the pathophysiology of macrophages including transcription factors, epigenetic regulation, differentiation, polarization, migration, cytokines, and chemokines production and function in diverse human disorders such as allergy, autoimmunity, inflammation, and cancer. This Special Issue aims to focus on both basic science and translational research as well as new advances in clinical evidence in order to have a more complete comprehension of macrophages and their impact on respiratory diseases.

We invite investigators to contribute original research articles and review articles that will address the molecular mechanism of macrophages in the immune response to respiratory diseases. Please note that pure clinical or model studies are unsuitable for this journal, but clinical submissions with biomolecular studies are welcome.

This special issue assists by our Topical Advisory Panel Member Dr. Camilla Margaroli （University of Alabama at Birmingham).

Dr. Yi-Giien Tsai
Dr. Chih-Hsing Hung
Dr. Hung-Ming Wu
Guest Editors

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Keywords

macrophage polarization
macrophage autophagy
macrophage phenotype
macrophage metabolism
macrophage function in diseases
respiratory diseases
innate immunity
allergy
inflammation

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Published Papers (10 papers)

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Research

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14 pages, 2586 KiB

Open AccessArticle

Dectin-1-Independent Macrophage Phagocytosis of Mycobacterium abscessus

by Alma E. Ochoa, Jack H. Congel, Jodi M. Corley, William J. Janssen, Jerry A. Nick, Kenneth C. Malcolm and Katherine B. Hisert

Int. J. Mol. Sci. 2023, 24(13), 11062; https://doi.org/10.3390/ijms241311062 - 4 Jul 2023

Cited by 1 | Viewed by 2284

Abstract

Mycobacterium abscessus, a species of nontuberculous mycobacteria (NTM), is an opportunistic pathogen that is readily cleared by healthy lungs but can cause pulmonary infections in people with chronic airway diseases. Although knowledge pertaining to molecular mechanisms of host defense against NTM is increasing, macrophage receptors that recognize M. abscessus remain poorly defined. Dectin-1, a C-type lectin receptor identified as a fungal receptor, has been shown to be a pathogen recognition receptor (PRR) for both M. tuberculosis and NTM. To better understand the role of Dectin-1 in host defense against M. abscessus, we tested whether blocking Dectin-1 impaired the uptake of M. abscessus by human macrophages, and we compared M. abscessus pulmonary infection in Dectin-1-deficient and wild-type mice. Blocking antibody for Dectin-1 did not reduce macrophage phagocytosis of M. abscessus, but did reduce the ingestion of the fungal antigen zymosan. Laminarin, a glucan that blocks Dectin-1 and other PRRs, caused decreased phagocytosis of both M. abscessus and zymosan. Dectin-1−/− mice exhibited no defects in the control of M. abscessus infection, and no differences were detected in immune cell populations between wild type and Dectin-1−/− mice. These data demonstrate that murine defense against M. abscessus pulmonary infection, as well as ingestion of M. abscessus by human macrophages, can occur independent of Dectin-1. Thus, additional PRR(s) recognized by laminarin participate in macrophage phagocytosis of M. abscessus. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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16 pages, 3626 KiB

Open AccessArticle

Inhibition of Macrophage-Specific CHIT1 as an Approach to Treat Airway Remodeling in Severe Asthma

by Piotr Sklepkiewicz, Barbara Dymek, Michal Mlacki, Agnieszka Zagozdzon, Magdalena Salamon, Anna Maria Siwińska, Marcin Piotr Mazurkiewicz, Natalia de Souza Xavier Costa, Marzena Mazur, Thais Mauad, Adam Gołębiowski, Karolina Dzwonek, Jakub Gołąb and Zbigniew Zasłona

Int. J. Mol. Sci. 2023, 24(5), 4719; https://doi.org/10.3390/ijms24054719 - 1 Mar 2023

Cited by 3 | Viewed by 2767

Abstract

Chitotriosidase (CHIT1) is an enzyme produced by macrophages that regulates their differentiation and polarization. Lung macrophages have been implicated in asthma development; therefore, we asked whether pharmacological inhibition of macrophage-specific CHIT1 would have beneficial effects in asthma, as it has been shown previously in other lung disorders. CHIT1 expression was evaluated in the lung tissues of deceased individuals with severe, uncontrolled, steroid-naïve asthma. OATD-01, a chitinase inhibitor, was tested in a 7-week-long house dust mite (HDM) murine model of chronic asthma characterized by accumulation of CHIT1-expressing macrophages. CHIT1 is a dominant chitinase activated in fibrotic areas of the lungs of individuals with fatal asthma. OATD-01 given in a therapeutic treatment regimen inhibited both inflammatory and airway remodeling features of asthma in the HDM model. These changes were accompanied by a significant and dose-dependent decrease in chitinolytic activity in BAL fluid and plasma, confirming in vivo target engagement. Both IL-13 expression and TGFβ1 levels in BAL fluid were decreased and a significant reduction in subepithelial airway fibrosis and airway wall thickness was observed. These results suggest that pharmacological chitinase inhibition offers protection against the development of fibrotic airway remodeling in severe asthma. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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14 pages, 5252 KiB

Open AccessArticle

Montelukast Increased IL-25, IL-33, and TSLP via Epigenetic Regulation in Airway Epithelial Cells

by Mei-Lan Tsai, Ming-Kai Tsai, Yi-Giien Tsai, Yu-Chih Lin, Ya-Ling Hsu, Yi-Ting Chen, Yi-Ching Lin and Chih-Hsing Hung

Int. J. Mol. Sci. 2023, 24(2), 1227; https://doi.org/10.3390/ijms24021227 - 8 Jan 2023

Cited by 4 | Viewed by 2715

Abstract

The epithelium-derived cytokines interleukin (IL)-25, IL-33, and thymic stromal lymphopoietin (TSLP) are important mediators that initiate innate type 2 immune responses in asthma. Leukotriene receptor antagonists (LTRAs) are commonly used to prevent asthma exacerbations. However, the effects of LTRAs on epithelium-derived cytokines expression in airway epithelial cells are unclear. This study aimed to investigate the effects of LTRAs on the expression of epithelium-derived cytokines in human airway epithelial cells and to explore possible underlying intracellular processes, including epigenetic regulation. A549 or HBE cells in air-liquid interface conditions were pretreated with different concentrations of LTRAs. The expression of epithelium-derived cytokines and intracellular signaling were investigated by real-time PCR, enzyme-linked immunosorbent assay, and Western blot. In addition, epigenetic regulation was investigated using chromatin immunoprecipitation analysis. The expression of IL-25, IL-33, and TSLP was increased under LTRAs treatment and suppressed by inhaled corticosteroid cotreatment. Montelukast-induced IL-25, IL-33, and TSLP expression were mediated by the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways and regulated by histone H3 acetylation and H3K36 and H3K79 trimethylation. LTRAs alone might increase inflammation and exacerbate asthma by inducing the production of IL-25, IL-33, and TSLP; therefore, LTRA monotherapy may not be an appropriate therapeutic option for asthma. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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15 pages, 1445 KiB

Open AccessArticle

Role of Myeloid Cell-Specific TLR9 in Mitochondrial DNA-Induced Lung Inflammation in Mice

by Kris Genelyn Dimasuay, Bruce Berg, Niccolette Schaunaman and Hong Wei Chu

Int. J. Mol. Sci. 2023, 24(2), 939; https://doi.org/10.3390/ijms24020939 - 4 Jan 2023

Cited by 3 | Viewed by 1981

Abstract

Mitochondrial dysfunction is common in various pathological conditions including obesity. Release of mitochondrial DNA (mtDNA) during mitochondrial dysfunction has been shown to play a role in driving the pro-inflammatory response in leukocytes including macrophages. However, the mechanisms by which mtDNA induces leukocyte inflammatory responses in vivo are still unclear. Moreover, how mtDNA is released in an obese setting has not been well understood. By using a mouse model of TLR9 deficiency in myeloid cells (e.g., macrophages), we found that TLR9 signaling in myeloid cells was critical to mtDNA-mediated pro-inflammatory responses such as neutrophil influx and chemokine production. mtDNA release by lung macrophages was enhanced by exposure to palmitic acid (PA), a major saturated fatty acid related to obesity. Moreover, TLR9 contributed to PA-mediated mtDNA release and inflammatory responses. Pathway analysis of RNA-sequencing data in TLR9-sufficient lung macrophages revealed the up-regulation of axon guidance molecule genes and down-regulation of metabolic pathway genes by PA. However, in TLR9-deficient lung macrophages, PA down-regulated axon guidance molecule genes, but up-regulated metabolic pathway genes. Our results suggest that mtDNA utilizes TLR9 signaling in leukocytes to promote lung inflammatory responses in hosts with increased PA. Moreover, TLR9 signaling is involved in the regulation of axon guidance and metabolic pathways in lung macrophages exposed to PA. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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14 pages, 4583 KiB

Open AccessArticle

Arsenic Induces M2 Macrophage Polarization and Shifts M1/M2 Cytokine Production via Mitophagy

by Chih-Hsing Hung, Hua-Yu Hsu, Hsin-Ying Clair Chiou, Mei-Lan Tsai, Huey-Ling You, Yu-Chih Lin, Wei-Ting Liao and Yi-Ching Lin

Int. J. Mol. Sci. 2022, 23(22), 13879; https://doi.org/10.3390/ijms232213879 - 10 Nov 2022

Cited by 5 | Viewed by 3424

Abstract

Arsenic is an environmental factor associated with epithelial–mesenchymal transition (EMT). Since macrophages play a crucial role in regulating EMT, we studied the effects of arsenic on macrophage polarization. We first determined the arsenic concentrations to be used by cell viability assays in conjunction with previous studies. In our results, arsenic treatment increased the alternatively activated (M2) macrophage markers, including arginase 1 (ARG-1) gene expression, chemokine (C-C motif) ligand 16 (CCL16), transforming growth factor-β1 (TGF-β1), and the cluster of differentiation 206 (CD206) surface marker. Arsenic-treated macrophages promoted A549 lung epithelial cell invasion and migration in a cell co-culture model and a 3D gel cell co-culture model, confirming that arsenic treatment promoted EMT in lung epithelial cells. We confirmed that arsenic induced autophagy/mitophagy by microtubule-associated protein 1 light-chain 3-II (LC3 II) and phosphor-Parkin (p-Parkin) protein markers. The autophagy inhibitor chloroquine (CQ) recovered the expression of the inducible nitric oxide synthase (iNOS) gene in arsenic-treated M1 macrophages, which represents a confirmation that arsenic indeed induced the repolarization of classically activated (M1) macrophage to M2 macrophages through the autophagy/mitophagy pathway. Next, we verified that arsenic increased M2 cell markers in mouse blood and lungs. This study suggests that mitophagy is involved in the arsenic-induced M1 macrophage switch to an M2-like phenotype. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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Review

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20 pages, 3589 KiB

Open AccessReview

The Role of Macrophages in Connective Tissue Disease-Associated Interstitial Lung Disease: Focusing on Molecular Mechanisms and Potential Treatment Strategies

by Chia-Chun Tseng, Ya-Wen Sung, Kuan-Yu Chen, Pin-Yi Wang, Chang-Yi Yen, Wan-Yu Sung, Cheng-Chin Wu, Tsan-Teng Ou, Wen-Chan Tsai, Wei-Ting Liao, Chung-Jen Chen, Su-Chen Lee, Shun-Jen Chang and Jeng-Hsien Yen

Int. J. Mol. Sci. 2023, 24(15), 11995; https://doi.org/10.3390/ijms241511995 - 26 Jul 2023

Cited by 4 | Viewed by 2202

Abstract

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe manifestation of CTD that leads to significant morbidity and mortality. Clinically, ILD can occur in diverse CTDs. Pathologically, CTD-ILD is characterized by various histologic patterns, such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. Abnormal immune system responses have traditionally been instrumental in its pathophysiology, and various changes in immune cells have been described, especially in macrophages. This article first briefly overviews the epidemiology, clinical characteristics, impacts, and histopathologic changes associated with CTD-ILD. Next, it summarizes the roles of various signaling pathways in macrophages or products of macrophages in ILD, helped by insights gained from animal models. In the following sections, this review returns to studies of macrophages in CTD-ILD in humans for an overall picture of the current understanding. Finally, we direct attention to potential therapies targeting macrophages in CTD-ILD in investigation or in clinical trials, as well as the future directions regarding macrophages in the context of CTD-ILD. Although the field of macrophages in CTD-ILD is still in its infancy, several lines of evidence suggest the potential of this area. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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26 pages, 1788 KiB

Open AccessReview

Macrophages Orchestrate Airway Inflammation, Remodeling, and Resolution in Asthma

by Rodney D. Britt, Jr., Anushka Ruwanpathirana, Maria L. Ford and Brandon W. Lewis

Int. J. Mol. Sci. 2023, 24(13), 10451; https://doi.org/10.3390/ijms241310451 - 21 Jun 2023

Cited by 14 | Viewed by 4074

Abstract

Asthma is a heterogenous chronic inflammatory lung disease with endotypes that manifest different immune system profiles, severity, and responses to current therapies. Regardless of endotype, asthma features increased immune cell infiltration, inflammatory cytokine release, and airway remodeling. Lung macrophages are also heterogenous in that there are separate subsets and, depending on the environment, different effector functions. Lung macrophages are important in recruitment of immune cells such as eosinophils, neutrophils, and monocytes that enhance allergic inflammation and initiate T helper cell responses. Persistent lung remodeling including mucus hypersecretion, increased airway smooth muscle mass, and airway fibrosis contributes to progressive lung function decline that is insensitive to current asthma treatments. Macrophages secrete inflammatory mediators that induce airway inflammation and remodeling. Additionally, lung macrophages are instrumental in protecting against pathogens and play a critical role in resolution of inflammation and return to homeostasis. This review summarizes current literature detailing the roles and existing knowledge gaps for macrophages as key inflammatory orchestrators in asthma pathogenesis. We also raise the idea that modulating inflammatory responses in lung macrophages is important for alleviating asthma. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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23 pages, 1401 KiB

Open AccessReview

Key Role of Mesenchymal Stromal Cell Interaction with Macrophages in Promoting Repair of Lung Injury

by Mirjana Jerkic, Katalin Szaszi, John G. Laffey, Ori Rotstein and Haibo Zhang

Int. J. Mol. Sci. 2023, 24(4), 3376; https://doi.org/10.3390/ijms24043376 - 8 Feb 2023

Cited by 15 | Viewed by 3346

Abstract

Lung macrophages (Mφs) are essential for pulmonary innate immunity and host defense due to their dynamic polarization and phenotype shifts. Mesenchymal stromal cells (MSCs) have secretory, immunomodulatory, and tissue-reparative properties and have shown promise in acute and chronic inflammatory lung diseases and in COVID-19. Many beneficial effects of MSCs are mediated through their interaction with resident alveolar and pulmonary interstitial Mφs. Bidirectional MSC-Mφ communication is achieved through direct contact, soluble factor secretion/activation, and organelle transfer. The lung microenvironment facilitates MSC secretion of factors that result in Mφ polarization towards an immunosuppressive M2-like phenotype for the restoration of tissue homeostasis. M2-like Mφ in turn can affect the MSC immune regulatory function in MSC engraftment and tissue reparatory effects. This review article highlights the mechanisms of crosstalk between MSCs and Mφs and the potential role of their interaction in lung repair in inflammatory lung diseases. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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18 pages, 716 KiB

Open AccessReview

Role of Macrophages in Air Pollution Exposure Related Asthma

by Chung-Hsiang Li, Mei-Lan Tsai, Hsin-Ying (Clair) Chiou, Yi-Ching Lin, Wei-Ting Liao and Chih-Hsing Hung

Int. J. Mol. Sci. 2022, 23(20), 12337; https://doi.org/10.3390/ijms232012337 - 15 Oct 2022

Cited by 14 | Viewed by 3522

Abstract

Asthma is a chronic inflammatory airway disease characterized by variable airflow obstruction, bronchial hyper-responsiveness, and airway inflammation. The chronic inflammation of the airway is mediated by many cell types, cytokines, chemokines, and inflammatory mediators. Research suggests that exposure to air pollution has a negative impact on asthma outcomes in adult and pediatric populations. Air pollution is one of the greatest environmental risks to health, and it impacts the lungs’ innate and adaptive defense systems. A major pollutant in the air is particulate matter (PM), a complex component composed of elemental carbon and heavy metals. According to the WHO, 99% of people live in air pollution where air quality levels are lower than the WHO air quality guidelines. This suggests that the effect of air pollution exposure on asthma is a crucial health issue worldwide. Macrophages are essential in recognizing and processing any inhaled foreign material, such as PM. Alveolar macrophages are one of the predominant cell types that process and remove inhaled PM by secreting proinflammatory mediators from the lung. This review focuses on macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants in asthma. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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21 pages, 1105 KiB

Open AccessReview

Plasticity towards Rigidity: A Macrophage Conundrum in Pulmonary Fibrosis

by Ezgi Sari, Chao He and Camilla Margaroli

Int. J. Mol. Sci. 2022, 23(19), 11443; https://doi.org/10.3390/ijms231911443 - 28 Sep 2022

Cited by 14 | Viewed by 5926

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic, and ultimately fatal diffuse parenchymal lung disease. The molecular mechanisms of fibrosis in IPF patients are not fully understood and there is a lack of effective treatments. For decades, different types of drugs such as immunosuppressants and antioxidants have been tested, usually with unsuccessful results. Although two antifibrotic drugs (Nintedanib and Pirfenidone) are approved and used for the treatment of IPF, side effects are common, and they only slow down disease progression without improving patients’ survival. Macrophages are central to lung homeostasis, wound healing, and injury. Depending on the stimulus in the microenvironment, macrophages may contribute to fibrosis, but also, they may play a role in the amelioration of fibrosis. In this review, we explore the role of macrophages in IPF in relation to the fibrotic processes, epithelial–mesenchymal transition (EMT), and their crosstalk with resident and recruited cells and we emphasized the importance of macrophages in finding new treatments. Full article

(This article belongs to the Special Issue Macrophages in Respiratory Diseases)

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