Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice

Simon D Pouwels*, Geert Zijlstra, Marco van der Toorn, Laura Hesse, Renee Gras, Nicolaas Hacken, ten, Dmitri V Krysko, Peter Vandenabeele, Maaike de Vries, Antoon J M van Oosterhout, Irene H Heijink, Martijn C Nawijn

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

96 Citaten (Scopus)

Samenvatting

Recent data indicate a role for airway epithelial necroptosis, a regulated form of necrosis, and the associated release of damage associated molecular patterns (DAMPs) in the development of COPD. DAMPs can activate pattern recognition receptors (PRRs), triggering innate immune responses. We hypothesized that cigarette smoke (CS)-induced epithelial necroptosis and DAMP release initiate airway inflammation in COPD. Human bronchial epithelial BEAS-2B cells were exposed to CS-extract (CSE) and necrotic cell death (membrane integrity by PI staining) and DAMP release (i.e. dsDNA, HMGB1, HSP70, mtDNA, ATP) were analyzed. Subsequently, BEAS-2B cells were exposed to DAMP-containing supernatant of CS-induced necrotic cells and the release of pro-inflammatory mediators (CXCL-8, IL-6) was evaluated. Further, mice were exposed to CS in the presence and absence of necroptosis inhibitor Necrostatin-1 and levels of DAMPs and inflammatory cell numbers were determined in bronchoalveolar lavage fluid. CSE induced a significant increase in the percentage of necrotic cells and DAMP release in BEAS-2B cells. Stimulation of BEAS-2B cells with supernatant of CS-induced necrotic cells induced a significant increase in the release of CXCL8 and IL-6, in a MyD88 dependent fashion. In mice, exposure of CS increased the levels of DAMPs and numbers of neutrophils in BAL fluid, which was statistically reduced upon treatment with Necrostatin-1. Together, we showed that CS exposure induces necrosis of bronchial epithelial cells and subsequent DAMP release in vitro, inducing the production of pro-inflammatory cytokines. In vivo, CS exposure induces neutrophilic airway inflammation that is sensitive to necroptosis inhibition.

Originele taal-2English
Pagina's (van-tot)L377-L386
Aantal pagina's10
TijdschriftAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume310
Nummer van het tijdschrift4
DOI's
StatusPublished - 30-dec-2015

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