Abstract
Neutrophils have a dual affect on epithelial pIgR/SC, the critical receptor for transcellular routing of mucosal IgA, but mechanisms of pIgR/SC upregulation remain elusive. Requirements of cytokine, redox, and signalling pathways for pIgR/SC production were assessed in human bronchial epithelial (Calu-3) cells cocultured with increasing numbers of blood neutrophils. Increased SC production was observed after incubation for 48 hrs with intermediate neutrophil numbers (1.25 to 2.5 × 106), was favoured by the elastase inhibitor SLPI, and correlated with increased TGF-β production. Exogenous TGF-β stimulated SC production with a maximal effect at 48 hrs and both TGF-β- and neutrophil-driven SC upregulation were dependent on redox balance and p38 MAP-kinase activation. This paper shows that activated neutrophils could upregulate epithelial pIgR/SC production through TGF-β-mediated activation of a redox-sensitive and p38 MAPK-dependent pathway. An imbalance between the two neutrophil-driven opposite mechanisms (SC upregulation and SC degradation) could lead to downregulation of pIgR/SC, as observed in severe COPD.
Highlights
The mucosal surfaces lining the respiratory tract are continuously exposed to potentially infectious agents, as well as environmental toxics and antigens
We previously showed that expression of polymeric Ig receptor (pIgR)/secretory component (SC) was strongly decreased in the bronchial epithelium from patients with severe Chronic obstructive pulmonary disease (COPD), and that this epithelial defect correlated with airflow limitation and with infiltration of submucosal glands by neutrophils [7]
These results indicated that this system allowed to address the two opposite effects of neutrophils on epithelial SC, and experiments were carried out to explore the mechanisms of SC upregulation by “nontoxic” numbers of neutrophils releasing elastase in a concentration range that could be observed in chronic airway neutrophilic diseases, for example, during exacerbations
Summary
The mucosal surfaces lining the respiratory tract are continuously exposed to potentially infectious agents, as well as environmental toxics and antigens. One first-line mechanism of the airway immune defense against inhaled antigens and microorganisms consists of secretory immunoglobulin A (SIgA), the predominant immunoglobulin isotype in mucosal secretions [1, 2]. Mucosal plasma cells produce IgA molecules mainly as polymers, linked through a joining chain. The pIgA-pIgR complexes are transported across epithelial cells up to the apical membrane where a proteolytic cleavage releases the main part of the extracellular domain of pIgR, known as secretory component (SC), remaining bound to pIgA to form SIgA [3] which assumes protective, antiinfectious functions within the mucosal lumen
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