An osteoclastogenesis system, the RANKL/RANK signalling pathway, contributes to aggravated allergic inflammation.

Abstract

As an osteoclast differentiation factor, receptor activator of NF-κB ligand (RANKL) is produced by various immune cells and may be involved in the pathogenesis of osteoporosis and inflammation. Although RANKL is expressed in most immune cells and tissues, it is not clear how this might affect allergic inflammation. The roles of RANKL in allergic rhinitis (AR) were analysed in an ovalbumin (OVA)-induced animal model, human subjects, and a human mast cell line (HMC-1). Small interfering RNA experiments were performed in an OVA-induced AR model. RANKL and RANKL receptor (RANK) were up-regulated in serum or nasal mucosal tissues of AR patients and AR mice. RANKL and RANK were colocalised in mast cells of nasal mucosa tissue. Depletion of RANKL by RANKL siRNA ameliorated AR symptoms and reduced AR-related biomarkers, including thymic stromal lymphopoietin (TSLP), IgE, histamine, and inflammatory cell infiltration, whereas recombinant RANKL increased AR responses and TSLP levels. In addition, functional deficiency of TSLP decreased AR responses induced by RANKL. In human mast cells, interaction of RANKL with RANK increased production of TSLP and inflammatory cytokines. Production of TSLP by RANKL stimulation was mediated through activation of the PI3K, MAPK, caspase-1, and NF-κB pathways. Furthermore, dexamethasone alleviated RANKL-induced inflammatory reactions in AR models. Collectively, these data suggest that RANKL may induce development of AR through up-regulation of TSLP.