The antimicrobial peptide S100A8/A9 produced by airway epithelium functions as a potent and direct regulator of macrophage phenotype and function

Elevated counts of alveolar macrophages and attenuated phagocytic capacity are associated with COPD. Factors governing macrophage phagocytosis are poorly understood. In this study we aimed to compare the influence of airway epithelial cell secretions from COPD and nonCOPD subjects on macrophage phagocytic activity, and the role of antimicrobial peptides (AMPs).Supernatants from nonCOPD and COPD small airway epithelial cell (SAEC) cultures exposed to Haemophilus influenzae (NTHi), were applied to human monocyte-derived macrophages (MDM) for assessment of their influence on phagocytosis. SAECs were analysed for changes in AMP expression by qRT-PCR and the influence of select AMPs on macrophage phenotype and function was assessed by flow cytometry and metabolic activity assay.Secretions from the apical and basolateral surface of NTHi-exposed SAECs from nonCOPD donors elicited superior phagocytic capacity of MDMs. Moreover, NTHi exposure led to a rapid increase in expression of a range of AMPs by nonCOPD SAECs, but this response was delayed in COPD SAECs. We demonstrate that treatment with AMPs β-defensin 2 and S100A8/A9 improved the phagocytic capacity of MDMs. In depth analysis of S100A8/A9 influence of MDMs revealed a role of this AMP in macrophage phenotype and function. Furthermore, we show that the expression of S100A8 and S100A9 is directly regulated by WNT/β-catenin signalling activity, a known deregulated pathway in COPD.In conclusion, for the first time, we demonstrate that airway epithelium from COPD subjects has a reduced capacity to support the phagocytic function of macrophages in response to acute NTHi exposure, and we identify the WNT/β-catenin signalling-modulated and epithelium-derived S100A8/A9 as a potent regulator of macrophage phenotype and function.

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Faculty Opinions recommendation of Pathogenesis of chronic rhinosinusitis with nasal polyps: role of IL-6 in airway epithelial cell dysfunction.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737631789.793574485 ◽

2020 ◽

Author(s):

Devyani Lal ◽

Shilpika Bajpai

Keyword(s):

Epithelial Cell ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Airway Epithelial Cell ◽

Airway Epithelial ◽

Cell Dysfunction

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Bioengineered airway epithelial grafts with mucociliary function based on collagen IV- and laminin-containing extracellular matrix scaffolds

European Respiratory Journal ◽

10.1183/13993003.01200-2019 ◽

2020 ◽

Vol 55 (6) ◽

pp. 1901200 ◽

Cited By ~ 2

Author(s):

Nick J.I. Hamilton ◽

Dani Do Hyang Lee ◽

Kate H.C. Gowers ◽

Colin R. Butler ◽

Elizabeth F. Maughan ◽

...

Keyword(s):

Extracellular Matrix ◽

Epithelial Cell ◽

Epithelial Cells ◽

Airway Epithelium ◽

Airway Epithelial Cell ◽

Collagen Iv ◽

Airway Epithelial ◽

Cell Adherence ◽

Bronchial Epithelial ◽

Mucociliary Function

Current methods to replace damaged upper airway epithelium with exogenous cells are limited. Existing strategies use grafts that lack mucociliary function, leading to infection and the retention of secretions and keratin debris. Strategies that regenerate airway epithelium with mucociliary function are clearly desirable and would enable new treatments for complex airway disease.Here, we investigated the influence of the extracellular matrix (ECM) on airway epithelial cell adherence, proliferation and mucociliary function in the context of bioengineered mucosal grafts. In vitro, primary human bronchial epithelial cells (HBECs) adhered most readily to collagen IV. Biological, biomimetic and synthetic scaffolds were compared in terms of their ECM protein content and airway epithelial cell adherence.Collagen IV and laminin were preserved on the surface of decellularised dermis and epithelial cell attachment to decellularised dermis was greater than to the biomimetic or synthetic alternatives tested. Blocking epithelial integrin α2 led to decreased adherence to collagen IV and to decellularised dermis scaffolds. At air–liquid interface (ALI), bronchial epithelial cells cultured on decellularised dermis scaffolds formed a differentiated respiratory epithelium with mucociliary function. Using in vivo chick chorioallantoic membrane (CAM), rabbit airway and immunocompromised mouse models, we showed short-term preservation of the cell layer following transplantation.Our results demonstrate the feasibility of generating HBEC grafts on clinically applicable decellularised dermis scaffolds and identify matrix proteins and integrins important for this process. The long-term survivability of pre-differentiated epithelia and the relative merits of this approach against transplanting basal cells should be assessed further in pre-clinical airway transplantation models.

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Glucose homeostasis across human airway epithelial cell monolayers: role of diffusion, transport and metabolism

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s00424-008-0576-4 ◽

2008 ◽

Vol 457 (5) ◽

pp. 1061-1070 ◽

Cited By ~ 45

Author(s):

Kameljit K. Kalsi ◽

Emma H. Baker ◽

Owen Fraser ◽

Yuen-Li Chung ◽

Oliver J. Mace ◽

...

Keyword(s):

Epithelial Cell ◽

Glucose Homeostasis ◽

Airway Epithelial Cell ◽

Airway Epithelial ◽

Diffusion Transport ◽

Cell Monolayers ◽

Human Airway ◽

Human Airway Epithelial Cell ◽

Epithelial Cell Monolayers

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Effect of inspired air conditions on exercise-induced bronchoconstriction and urinary CC16 levels in athletes

Journal of Applied Physiology ◽

10.1152/japplphysiol.00113.2011 ◽

2011 ◽

Vol 111 (4) ◽

pp. 1059-1065 ◽

Cited By ~ 39

Author(s):

C. Bolger ◽

E. Tufvesson ◽

S. D. Anderson ◽

G. Devereux ◽

J. G. Ayres ◽

...

Keyword(s):

Epithelial Cell ◽

Relative Humidity ◽

Airway Epithelium ◽

Cell Injury ◽

Airway Epithelial Cell ◽

Airway Epithelial ◽

Maximal Aerobic Capacity ◽

Humid Air ◽

Exercise Tests ◽

Exercise Induced

Injury to the airway epithelium has been proposed as a key susceptibility factor for exercise-induced bronchoconstriction (EIB). Our goals were to establish whether airway epithelial cell injury occurs during EIB in athletes and whether inhalation of warm humid air inhibits this injury. Twenty-one young male athletes (10 with a history of EIB) performed two 8-min exercise tests near maximal aerobic capacity in cold dry (4°C, 37% relative humidity) and warm humid (25°C, 94% relative humidity) air on separate days. Postexercise changes in urinary CC16 were used as a biomarker of airway epithelial cell perturbation and injury. Bronchoconstriction occurred in eight athletes in the cold dry environment and was completely blocked by inhalation of warm humid air [maximal fall in forced expiratory volume in 1 s = 18.1 ± 2.1% (SD) in cold dry air and 1.7 ± 0.8% in warm humid air, P < 0.01]. Exercise caused an increase in urinary excretion of CC16 in all subjects ( P < 0.001), but this rise in CC16 was blunted following inhalation of warm humid air [median CC16 increase pre- to postchallenge = 1.91 and 0.35 ng/μmol in cold dry and warm humid air, respectively, in athletes with EIB ( P = 0.017) and 1.68 and 0.48 ng/μmol in cold dry and warm humid air, respectively, in athletes without EIB ( P = 0.002)]. The results indicate that exercise hyperpnea transiently disrupts the airway epithelium of all athletes (not only in those with EIB) and that inhalation of warm moist air limits airway epithelial cell perturbation and injury.

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P203 Media impact on phenotype and function of an established airway epithelial cell line

Journal of Cystic Fibrosis ◽

10.1016/s1569-1993(20)30537-3 ◽

2020 ◽

Vol 19 ◽

pp. S113-S114

Author(s):

G. Livnat-Levanon ◽

J. Moncivaiz ◽

L. Strecker ◽

A. Ostmann ◽

J. Clancy ◽

...

Keyword(s):

Epithelial Cell ◽

Cell Line ◽

Airway Epithelial Cell ◽

Epithelial Cell Line ◽

Airway Epithelial ◽

Media Impact ◽

And Function

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Multiple TLRs activate EGFR via a signaling cascade to produce innate immune responses in airway epithelium

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00025.2008 ◽

2008 ◽

Vol 294 (6) ◽

pp. L1068-L1075 ◽

Cited By ~ 165

Author(s):

Jonathan L. Koff ◽

Matt X. G. Shao ◽

Iris F. Ueki ◽

Jay A. Nadel

Keyword(s):

Epithelial Cell ◽

Epithelial Cells ◽

Immune Responses ◽

Nadph Oxidase ◽

Airway Epithelium ◽

Airway Epithelial Cell ◽

Innate Immune ◽

Signaling Cascade ◽

Airway Epithelial ◽

Innate Immune Responses

Toll-like receptors (TLRs) are critical for the recognition of inhaled pathogens that deposit on the airway epithelial surface. The epithelial response to pathogens includes signaling cascades that activate the EGF receptor (EGFR). We hypothesized that TLRs communicate with EGFR via epithelial signaling to produce certain innate immune responses. Airway epithelium expresses the highest levels of TLR2, TLR3, TLR5, and TLR6, and here we found that ligands for these TLRs increased IL-8 and VEGF production in normal human bronchial epithelial cells. These effects were prevented by treatment with a selective inhibitor of EGFR phosphorylation (AG-1478), a metalloprotease (MP) inhibitor, a reactive oxygen species (ROS) scavenger, and an NADPH oxidase inhibitor. In an airway epithelial cell line (NCI-H292), TNF-α-converting enzyme (TACE) small interfering RNA (siRNA) was used to confirm that TACE is the MP involved in TLR ligand-induced IL-8 and VEGF production. We show that transforming growth factor (TGF)-α is the EGFR ligand in this signaling cascade by using TGF-α neutralizing antibody and by showing that epithelial production of TGF-α occurs in response to TLR ligands. Dual oxidase 1 (Duox1) siRNA was used to confirm that Duox1 is the NADPH oxidase involved in TLR ligand-induced IL-8 and VEGF production. We conclude that multiple TLR ligands induce airway epithelial cell production of IL-8 and VEGF via a Duox1→ ROS→ TACE→ TGF-α→ EGFR phosphorylation pathway. These results show for the first time that multiple TLRs in airway epithelial cells produce innate immune responses by activating EGFR via an epithelial cell signaling cascade.

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