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RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma.

ABSTRACT: Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.

SUBMITTER: Arikkatt J

PROVIDER: S-EPMC5243115 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma.

Arikkatt Jaisy J Ullah Md Ashik MA Short Kirsty Renfree KR Zhang Vivan V Gan Wan Jun WJ Loh Zhixuan Z Werder Rhiannon B RB Simpson Jennifer J Sly Peter D PD Mazzone Stuart B SB Spann Kirsten M KM Ferreira Manuel Ar MA Upham John W JW Sukkar Maria B MB Phipps Simon S

eLife 20170118

Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (<i>RAGE</i>) are risk factors for asthma development. Here, we show that R ...[more]

PMID: 28099113

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Project description:Background: Membranous nephropathy (MN) is a specific entity of glomerulonephritis, and its glomerular inflammation is characterized by the deposition of immune complexes in the glomerular basement membrane and proteinuria. However, the molecular mechanisms underlying the glomerular inflammation of MN are not fully understood. This study was designed to investigate the role of clusterin (CLU) in the development of MN using a mouse model of cationic bovine serum albumin (cBSA)-induced MN.Methods: Both wild-type C57BL/6j (WT) and CLU-knockout C57BL/6j (CLU-KO) mice were immunized with cBSA. The kidney function was determined by the levels of serum creatinine (SCr), blood urea nitrogen (BUN) and urinary protein. MN and glomerular deposits of CLU, complement C3 and immunoglobulins (Igs) were determined by histological analyses. Serum proteins were analyzed by the enzyme-linked immunosorbent assay, Western blot and liquid chromatography-mass spectrometry.Results: Here, we showed that after cBSA immunization, SCr and proteinuria were increased in CLU-KO mice but not in WT mice. Similarly, severe glomerular atrophy and mesangial expansion along with C3 deposit were only found in the kidneys of CLU-KO mice but not in WT mice. However, there were no differences of serum IgG and complement 3 levels between CLU-KO and WT mice. In the serum of WT mice, CLU bound to anti-cBSA IgG, complements (eg, C8), proteinase/protease inhibitors and antioxidative proteins to form a complex, and incubation with WT serum reduced the complement-dependent lysis of podocytes in cultures.Conclusion: Our data suggest that a CLU deficiency induces cBSA-initiated glomerular inflammation of MN in a disease-resistant strain of mice, suggesting an anti-glomerular inflammatory function of CLU in the resistance to MN development. This function may be at least in part due to the formation of CLU-anti-cBSA Igs complex that prevents glomerular inflammation or injury in the disease-resistant mice.

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RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma.

Publications

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma.

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