Loss of lung WWOX expression causes neutrophilic inflammation

Sunit Singla, Jiwang Chen, Shruthi Sethuraman, Justin R. Sysol, Amulya Gampa, Shuangping Zhao, Roberto F. Machado

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The tumor suppressor WW domain-containing oxidoreductase (WWOX) exhibits regulatory interactions with an array of transcription factors and signaling molecules that are positioned at the well-known crossroads between inflammation and cancer. WWOX is also subject to downregulation by genotoxic environmental exposures, making it of potential interest to the study of lung pathobiology. Knockdown of lung WWOX expression in mice was observed to cause neutrophil influx and was accompanied by a corresponding vascular leak and inflammatory cytokine production. In cultured human alveolar epithelial cells, loss of WWOX expression resulted in increased c-Jun-and IL-8-dependent neutrophil chemotaxis toward cell monolayers. WWOX was observed to directly interact with c-Jun in these cells, and its absence resulted in increased nuclear translocation of c-Jun. Finally, inhibition of the c-Jun-activating kinase JNK abrogated the lung neutrophil influx observed during WWOX knockdown in mice. Altogether, these observations represent a novel mechanism of pulmonary neutrophil influx that is highly relevant to the pathobiology and potential treatment of a number of different lung inflammatory conditions.

Original languageEnglish (US)
Pages (from-to)L903-L911
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume312
Issue number6
DOIs
StatePublished - Jun 5 2017
Externally publishedYes

Keywords

  • Inflammation
  • Lung injury
  • Neutrophils
  • WWOX

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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