Skip to main content

ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1543729

Alpha-defensins increase NTHi binding but not engulfment by the macrophages enhancing airway inflammation in Alpha-1 Antitrypsin Deficiency

Provisionally accepted
Jungnam Lee Jungnam Lee 1Naweed Mohammad Naweed Mohammad 1*Kyudong Han Kyudong Han 2,3Tammy Flagg-Dowie Tammy Flagg-Dowie 1*Maria Magallon Maria Magallon 1*Mark Brantly Mark Brantly 1Karina A Serban Karina A Serban 1,4*
  • 1 Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida, United States
  • 2 Department of Microbiology, Dankook University, Cheonan, Republic of Korea
  • 3 Center for Bio-Medical Engineering Core Facility, Dankook University, Cheonan, Republic of Korea
  • 4 Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, Colorado, United States

The final, formatted version of the article will be published soon.

    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 proinflammatory 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 αdefensin-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.

    Keywords: Alpha defensins, alpha 1 antitrypsin (AAT), AAT deficiency (AATD), Neutrophils, Macrophages, Cytokines, Phagocytosis Font: Italic Formatted: Right: 0.25" Deleted: ¶ Font color: Custom Color(RGB(33, 33

    Received: 11 Dec 2024; Accepted: 27 Jan 2025.

    Copyright: © 2025 Lee, Mohammad, Han, Flagg-Dowie, Magallon, Brantly and Serban. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Naweed Mohammad, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida, United States
    Tammy Flagg-Dowie, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida, United States
    Maria Magallon, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida, United States
    Karina A Serban, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, Gainesville, Florida, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.