Downregulation of Sfrp5 in insulin resistant rats promotes macrophage-mediated pulmonary inflammation through activation of Wnt5a/JNK1 signaling

Biochem Biophys Res Commun. 2018 Oct 28;505(2):498-504. doi: 10.1016/j.bbrc.2018.09.070. Epub 2018 Sep 26.

Abstract

Background: Insulin resistance (IR), a common co-morbidity of chronic obstructive pulmonary disease (COPD), aggravates airway inflammation in COPD patients, but its mechanism is unclear. Sfrp5, a novel anti-inflammatory adipocytokine, inhibits macrophage-mediated inflammation of adipose tissue and abrogates IR. However, few studies have been conducted on the regulatory role of Sfrp5 in lung inflammation.

Methods: In the present study, 30 SD rats were divided into two groups: the normal food (NF) group and the high-fat diet (HFD) group. Oral glucose tolerance test (OGTT) and insulin release test were performed to assess whether a successful IR rat model was established. The expression of Sfrp5 and key downstream moleculars of Wnt5a/JNKl signaling was detected. Lung tissue pathomorphology and macrophage activation were observed. In addition, we counted the number of inflammatory cells and measured inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In vitro, rat lung macrophages were isolated and treated with Wnt5a, Sfrp5, and/or JNK inhibitor SP600125. JNK activity and inflammatory cytokines expression were examined.

Results: We found that in a rat model of IR, Sfrp5 expression of lung tissue was downregulated, while the Wnt5a/JNKl pathway was activated and the lung inflammatory response was enhanced. Meanwhile, Sfrp5 significantly suppressed Wnt5a/JNKl-induced macrophage activation.

Conclusions: Collectively, IR reduces Sfrp5 expression of lung tissue and activates the Wnt5a/JNK1 pathway, promoting macrophage activation and contributing to the lung's inflammatory response. In contrast, Sfrp5 suppresses the inflammatory response by inhibiting the Wnt5a/JNKl pathway, which could be a target of treatment of COPD.

Keywords: Airway inflammation; Insulin resistance; Lung macrophages; Sfrp5; Wnt5a/JNK1 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / metabolism*
  • Animals
  • Down-Regulation
  • Insulin Resistance*
  • Macrophage Activation
  • Macrophages / metabolism*
  • Male
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Pneumonia / enzymology
  • Pneumonia / metabolism*
  • Pneumonia / pathology
  • Rats, Sprague-Dawley
  • Signal Transduction*
  • Wnt-5a Protein / metabolism

Substances

  • Adipokines
  • Wnt-5a Protein
  • Wnt5a protein, rat
  • secreted frizzled-related protein 5, rat
  • Mitogen-Activated Protein Kinase 8