Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiency
Neutrophilic inflammation and a high level of free α-defensins are main features of chronic airway inflammation in alpha-1 antitrypsin-deficient (AATD) individuals. Despite the antimicrobial activities of α-defensins by direct bacterial killing and by modulation of immune responses, AATD individuals...
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| Format: | Article |
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1543729/full |
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| author | Jungnam Lee Naweed Mohammad Kyudong Han Kyudong Han Tammy Flagg-Dowie Maria Magallon Mark L. Brantly Karina A. Serban Karina A. Serban |
| author_facet | Jungnam Lee Naweed Mohammad Kyudong Han Kyudong Han Tammy Flagg-Dowie Maria Magallon Mark L. Brantly Karina A. Serban Karina A. Serban |
| author_sort | Jungnam Lee |
| collection | DOAJ |
| description | Neutrophilic inflammation and a high level of free α-defensins are main features of chronic airway inflammation in alpha-1 antitrypsin-deficient (AATD) individuals. Despite the antimicrobial activities of α-defensins by direct bacterial killing and by modulation of immune responses, AATD individuals are paradoxically burdened by recurrent exacerbation triggered by bacterial infections, frequently with nontypeable Haemophilus influenzae (NTHi). Previous studies demonstrated that high, rather than low α-defensin level could modulate the local pro-inflammatory milieu of bronchial epithelial cells and macrophages promoting chronic inflammation and lower pathogen phagocytosis. IgG-mediated phagocytosis and NTHi adherence, engulfment and phagocytosis were measured in human alveolar macrophages and monocyte-derived macrophages (MDM) isolated from patients with AATD and from healthy individuals. A high concentration of free α-defensins induced NTHi adherence to MDMs but decreased IgG-mediated phagocytosis by MDMs. The decreased phagocytosis was associated with TLR4 activation, downstream signaling via NF-κB p65 and marked increased secretion of inflammatory cytokines, CXCL8, IL-1b, and TNFα by the α-defensin-treated and NTHi-infected MDMs. Exogenous AAT treatment and TLR4 inhibitor decreased TNFα expression in α-defensin-treated cells. Dampening the downstream effects of a high concentration of α-defensins may render AAT and TLR4 inhibitors as potential therapies to decrease NTHi colonization and increase its clearance by phagocytosis in AATD individuals. |
| format | Article |
| id | doaj-art-ff103f4522044346ac8f844038e1ef95 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-ff103f4522044346ac8f844038e1ef952025-02-12T07:27:23ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15437291543729Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiencyJungnam Lee0Naweed Mohammad1Kyudong Han2Kyudong Han3Tammy Flagg-Dowie4Maria Magallon5Mark L. Brantly6Karina A. Serban7Karina A. Serban8Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Microbiology, College of Bio-convergence, Dankook University, Cheonan, Republic of KoreaCenter for Bio-Medical Engineering Core Facility, Dankook University, Cheonan, Republic of KoreaDivision of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United StatesDivision of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, FL, United StatesDepartment of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, United StatesNeutrophilic inflammation and a high level of free α-defensins are main features of chronic airway inflammation in alpha-1 antitrypsin-deficient (AATD) individuals. Despite the antimicrobial activities of α-defensins by direct bacterial killing and by modulation of immune responses, AATD individuals are paradoxically burdened by recurrent exacerbation triggered by bacterial infections, frequently with nontypeable Haemophilus influenzae (NTHi). Previous studies demonstrated that high, rather than low α-defensin level could modulate the local pro-inflammatory milieu of bronchial epithelial cells and macrophages promoting chronic inflammation and lower pathogen phagocytosis. IgG-mediated phagocytosis and NTHi adherence, engulfment and phagocytosis were measured in human alveolar macrophages and monocyte-derived macrophages (MDM) isolated from patients with AATD and from healthy individuals. A high concentration of free α-defensins induced NTHi adherence to MDMs but decreased IgG-mediated phagocytosis by MDMs. The decreased phagocytosis was associated with TLR4 activation, downstream signaling via NF-κB p65 and marked increased secretion of inflammatory cytokines, CXCL8, IL-1b, and TNFα by the α-defensin-treated and NTHi-infected MDMs. Exogenous AAT treatment and TLR4 inhibitor decreased TNFα expression in α-defensin-treated cells. Dampening the downstream effects of a high concentration of α-defensins may render AAT and TLR4 inhibitors as potential therapies to decrease NTHi colonization and increase its clearance by phagocytosis in AATD individuals.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1543729/fullalpha defensinsalpha 1 antitrypsin (AAT)AAT deficiency (AATD)neutrophilsmacrophagescytokines |
| spellingShingle | Jungnam Lee Naweed Mohammad Kyudong Han Kyudong Han Tammy Flagg-Dowie Maria Magallon Mark L. Brantly Karina A. Serban Karina A. Serban Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiency Frontiers in Immunology alpha defensins alpha 1 antitrypsin (AAT) AAT deficiency (AATD) neutrophils macrophages cytokines |
| title | Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiency |
| title_full | Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiency |
| title_fullStr | Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiency |
| title_full_unstemmed | Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiency |
| title_short | Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 antitrypsin deficiency |
| title_sort | alpha defensins increase nthi binding but not engulfment by the macrophages enhancing airway inflammation in alpha 1 antitrypsin deficiency |
| topic | alpha defensins alpha 1 antitrypsin (AAT) AAT deficiency (AATD) neutrophils macrophages cytokines |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1543729/full |
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