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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-?B 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-?B 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.

SUBMITTER: Nam SY

PROVIDER: S-EPMC6514295 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Project description:Inflammatory mechanisms influence tumorigenesis and metastatic progression even in cancers whose aetiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. For instance, prostate cancer metastasis is associated with the infiltration of lymphocytes into advanced tumours and the upregulation of two tumour-necrosis-factor family members: receptor activator of nuclear factor-?B (RANK) ligand (RANKL) and lymphotoxin. But the source of RANKL and its role in metastasis have not been established. RANKL and its receptor RANK control the proliferation of mammary lobuloalveolar cells during pregnancy through inhibitor of nuclear factor-?B (I?B) kinase-? (IKK-?), a protein kinase that is needed for the self-renewal of mammary cancer progenitors and for prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKK-? are also involved in mammary/breast cancer metastasis. Indeed, RANK signalling in mammary carcinoma cells that overexpress the proto-oncogene Erbb2 (also known as Neu), which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of Erbb2-transformed carcinoma cells also required CD4(+)CD25(+) T cells, whose major pro-metastatic function was RANKL production. Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcription factor produced by regulatory T cells, and were located next to smooth muscle actin (SMA)(+) stromal cells in mouse and human breast cancers. The dependence of pulmonary metastasis on T cells was replaceable by exogenous RANKL, which also stimulated pulmonary metastasis of RANK(+) human breast cancer cells. These results are consistent with the adverse impact of tumour-infiltrating CD4(+) or FOXP3(+) T cells on human breast cancer prognosis and suggest that the targeting of RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.

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

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