Resistin signaling via NF-κB pathway plays a key role in obesity-induced and -aggravated asthma.

Resistin, an adipokine secreted by adipocytes and immune cells, and NF-κB, a pro-inflammatory transcription factor involved in immune regulation, have been implicated in obesity-induced asthma. C57BL/6 mice were assigned to either an ovalbumin-induced asthma model or an obesity group. The mice were treated with CDN1163 (SERCA activator; administered 12 times over 3 weeks), resistin recombinant protein (4 times over 2 weeks), resistin blocking antibody (3 times per week), and/or an NF-κB inhibitor (MG132; 3 times per week). For in vitro experiments, Beas-2B bronchial epithelial cells were treated with lipopolysaccharide (LPS), insulin, siRNAs targeting resistin, Retnlα, and Retnlβ, and NF-κB inhibitor. In murine model, CDN1163 ameliorated both obesity-induced and -aggravated asthma by improving airway hyper-responsiveness, airway inflammation, tissue remodeling, and fibrosis, and decreasing inflammatory cytokines, including NF-κB. Exogenous resistin stimulation via administration of recombinant resistin protein significantly increased NF-κB expression, whereas the resistin-neutralizing antibody reversed this effect and ameliorated features of asthma. Notably, NF-κB inhibition significantly alleviated airway hyper-responsiveness, inflammation, and fibrosis, but did not alter resistin levels. In vitro experiments showed that resistin-targeting siRNAs significantly decreased LPS- and insulin-induced pro-inflammatory cytokine production. NF-κB inhibitor decreased the levels of inflammatory cytokines, but not resistin. In human cohort study, resistin expression was significantly higher in obese asthma compared to asthma patients with normal BMI. Resistin signaling via the NF-κB pathway may contribute to obesity-induced and -aggravated asthma and may represent a potential therapeutic target.