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

Abstract

Background and Purpose: 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. Experimental Approach: 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. Key Results: 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. Conclusion and Implications: Collectively, these data suggest that RANKL may induce development of AR through up-regulation of TSLP. 1 | INTRODUCTION Allergic rhinitis (AR) is a Type I hypersensitive inflammatory immune responses in the nasal mucosa caused by inhaled allergens, such as mould, animal dander, and pollen (Rondón et al., 2012). AR is induced by an allergen cross-linking with IgE bound to a mast cell. Mast cells, which lead to acute clinical symptoms with early nasal responses such as itching, sneezing, congestion, and rhinorrhea by IgE-dependent release of histamine, leukotrienes, and prostaglandins (May & Dolen, 2017), have a central role in inflammatory allergic reactions through the infiltration of inflammatory cells by the production of thymic stromal lymphopoietin (TSLP) and Th2 cytokines (

Effects of histamine on human periodontal ligament fibroblasts under simulated orthodontic pressure

“…Schroeder et al found an increasing effect on RANKL expression during the first 72 h of orthodontic force treatment [6]. Nam et al reported an upregulation of RANKL in the serum and nasal mucosal tissue of allergic rhinitis patients [52]. This is in line with our data, as RANKL gene expression and protein expression are significantly increased when adding histamine.…”

Mast Cells Trigger Disturbed Bone Healing in Osteoporotic Mice

“…However, because supernatants were collected 1 hour after stimulation, RANKL and IL-6 release may be insufficient or delayed. Both factors are mainly de novo synthesized by mast cells, (3,(93)(94)(95)(96) which is why longer stimulation might lead to increased RANKL and IL-6 release. It was previously shown that estrogen modulates RANKL expression via ERα on osteoblastic cells, (97) which might similarly apply to mast cells, because we found mast cell ERα expressed in the fracture callus.…”

Epothilone B prevents lipopolysaccharide-induced inflammatory osteolysis through suppressing osteoclastogenesis via STAT3 signaling pathway

“…Studies of the underlying mechanism have revealed that inactive NF-κB subunits are retained in the cytoplasm by inhibitory IκB. The activated IKK complex catalyses the phosphorylation and subsequent degradation of IκB, which releases NF-κB p65/Rel A to translocate to the nucleus and initiate target gene transcription [28,29]. Moreover, previous studies have revealed that activation of STAT3 pathway was a crucial promoter in osteoclast formation and inflammatory bone loss [30].…”