Leptin aggravates house dust mite-induced airway inflammation by accelerating macrophage necroptosis

Leptin is a proinflammatory adipokine asthmatic biomarker and macrophage necroptosis are previously reported to be involved in asthmatic airway inflammation. However, whether leptin worsen airway inflammation via mediating macrophage necroptosis remains elusive. We investigated the role of the leptin on regulating macrophage necroptosis in the development of asthma.

Leptin - deficient (ob/ob) mice, recombinant mouse leptin protein systematically administration and high-fat diet (HFD) - induced obesity protocols were used to establish a house dust mite (HDM) - induce mouse asthma model. Histopathological staining, ELISA and airway hyperresponsiveness (AHR) detection were performed to evaluate airway inflammation. RNA-sequencing (RNA-seq) of sorted alveolar macrophages (AMs), in vivo macrophage depletion by clodronate liposomes and in vitro cell experiments were performed to elucidate the underlying mechanism.

Deficiency of Leptin alleviated HDM - induced airway inflammation and AHR, however, exogenous leptin supplement and HFD promoted asthmatic inflammation. RNA-seq analysis revealed that leptin was involved in necroptosis signaling pathway. Deletion of Leptin inhibited phosphor-receptor-interacting protein kinase 3 (p-RIPK3), phosphor-mixed lineage kinase domain-like (p-MLKL), cleaved caspase 3, and inflammation marker CD86 and CD206 expression in HDM - treated lung, and further exogenous leptin and obesity - associated leptin enhanced expression of necroptosis marker in lung. Moreover, leptin synergizing with HDM upregulated expression of p-RIPK3, and p-MLKL, apoptosis levels and IL-6 secretion in macrophages in vitro. And AMs depletion during HDM challenge reversed the protective effect of leptin deletion.

Leptin exacerbates HDM-induced airway inflammation via enhancing macrophage necroptosis, which might have promising intervention potential.