Dataset Information

Long noncoding RNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in alveolar hemorrhage associated with systemic lupus erythematosus.

ABSTRACT:

Background

Dysregulated long noncoding RNA (lncRNA) expression with increased apoptosis has been demonstrated in systemic lupus erythematosus (SLE) patients with alveolar hemorrhage (AH). SNHG16, a lncRNA, can enhance pulmonary inflammation by sponging microRNAs, and upregulate toll-like receptor 4 (TLR4) expression via stabilizing its mRNAs. TRAF6, a TLR4 downstream signal transducer, can induce autophagy and NETosis formation. In this study, we investigated whether SNHG16 could regulate TLR4-mediated autophagy and NETosis formation in SLE-associated AH.

Methods

Expression of SNHG16, TLR4 and TRAF6 and cell death processes were examined in lung tissues and peripheral blood (PB) leukocytes from AH patients associated with SLE and other autoimmune diseases, and in the lungs and spleen from a pristane-induced C57BL/6 mouse AH model. SNHG16-overexpressed or -silenced alveolar and myelocytic cells were stimulated with lipopolysaccharide (LPS), a TLR4 agonist, for analyzing autophagy and NETosis, respectively. Pristane-injected mice received the intra-pulmonary delivery of lentivirus (LV)-SNHG16 for overexpression and prophylactic/therapeutic infusion of short hairpin RNA (shRNA) targeting SNHG16 to evaluate the effects on AH. Renal SNHG16 expression was also examined in lupus nephritis (LN) patients and a pristane-induced BALB/c mouse LN model.

Results

Up-regulated SNHG16, TLR4 and TRAF6 expression with increased autophagy and NETosis was demonstrated in the SLE-AH lungs. In such patients, up-regulated SNHG16, TLR4 and TRAF6 expression was found in PB mononuclear cells with increased autophagy and in PB neutrophils with increased NETosis. There were up-regulated TLR4 expression and increased LPS-induced autophagy and NETosis in SNHG16-overexpressed cells, while down-regulated TLR4 expression and decreased LPS-induced autophagy and NETosis in SNHG16-silenced cells. Pristane-injected lung tissues had up-regulated SNHG16, TLR4/TRAF6 levels and increased in situ autophagy and NETosis formation. Intra-pulmonary LV-SNHG16 delivery enhanced AH through up-regulating TLR4/TRAF6 expression with increased cell death processes, while intra-pulmonary prophylactic and early therapeutic sh-SNHG16 delivery suppressed AH by down-regulating TLR4/TRAF6 expression with reduced such processes. In addition, there was decreased renal SNHG16 expression in LN patients and mice.

Conclusions

Our results demonstrate that lncRNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in the human and mouse AH lungs, and provide a therapeutic potential of intra-pulmonary delivery of shRNA targeting SNHG16 in this SLE-related lethal manifestation.

SUBMITTER: Hsieh YT

PROVIDER: S-EPMC10496234 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Long noncoding RNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in alveolar hemorrhage associated with systemic lupus erythematosus.

Hsieh Yu-Tung YT Chen Yi-Cheng YC Chou Yu-Chi YC Kuo Pin-Yu PY Yen Yi-Ting YT Tsai Hung-Wen HW Wang Chrong-Reen CR

Journal of biomedical science 20230912 1

<h4>Background</h4>Dysregulated long noncoding RNA (lncRNA) expression with increased apoptosis has been demonstrated in systemic lupus erythematosus (SLE) patients with alveolar hemorrhage (AH). SNHG16, a lncRNA, can enhance pulmonary inflammation by sponging microRNAs, and upregulate toll-like receptor 4 (TLR4) expression via stabilizing its mRNAs. TRAF6, a TLR4 downstream signal transducer, can induce autophagy and NETosis formation. In this study, we investigated whether SNHG16 could regulat ...[more]

PMID: 37700342

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Project description:Neutrophil Extracellular Traps (NETs) have been implicated in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) pathogenesis. The myeloperoxidase-deoxyribonucleic acid (MPO-DNA) complex and nucleosomes are serum markers of NETosis. The aim of this study was to assess these NETosis parameters as markers for SLE and APS diagnosis and their association with clinical features and disease activity. A total of 138 people were included in the cross-sectional study: 30 with SLE without APS, 47 with SLE and APS, 41 patients with primary antiphospholipid syndrome (PAPS), and 20 seemingly healthy individuals. Serum MPO-DNA complex and nucleosome levels were determined via an enzyme-linked immunosorbent assay (ELISA). Informed consent was obtained from all subjects involved in the study. The Ethics Committee of the V.A. Nasonova Research Institute of Rheumatology (Protocol No. 25 dated 23 December 2021) approved the study. In patients with SLE without APS, the levels of the MPO-DNA complex were significantly higher compared to patients with SLE with APS, with PAPS, and healthy controls (p < 0.0001). Among patients with a reliable diagnosis of SLE, 30 had positive values of the MPO-DNA complex, of whom 18 had SLE without APS, and 12 had SLE with APS. Patients with SLE and positive MPO-DNA complex levels were significantly more likely to have high SLE activity (χ2 = 5.25, p = 0.037), lupus glomerulonephritis (χ2 = 6.82, p = 0.009), positive antibodies to dsDNA (χ2 = 4.82, p = 0.036), and hypocomplementemia (χ2 = 6.72, p = 0.01). Elevated MPO-DNA levels were observed in 22 patients with APS: 12 with SLE with APS and 10 with PAPS. There were no significant associations between positive levels of the MPO-DNA complex and clinical and laboratory manifestations of APS. The concentration of nucleosomes was significantly lower in the group of SLE patients (±APS) compared to controls and PAPS (p < 0.0001). In SLE patients, the frequency of low nucleosome levels was associated with high SLE activity (χ2 = 13.4, p < 0.0001), lupus nephritis (χ2 = 4.1, p = 0.043), and arthritis (χ2 = 3.89, p = 0.048). An increase in the specific marker of NETosis, the MPO-DNA complex, was found in the blood serum of SLE patients without APS. Elevated levels of the MPO-DNA complex can be regarded as a promising biomarker of lupus nephritis, disease activity, and immunological disorders in SLE patients. Lower levels of nucleosomes were significantly associated with SLE (±APS). Low nucleosome levels were more common in patients with high SLE activity, lupus nephritis, and arthritis.

Project description:BackgroundDiffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). The current knowledge of the prognostic factors for SLE-associated DAH is controversial. This meta-analysis was undertaken to investigate the relevant risk factors for mortality in SLE-associated DAH.MethodsStudies were searched from PubMed, EMBASE, and Web of Science databases published up to May 27, 2020, and were selected or removed according to the inclusion and exclusion criteria. Two reviewers extracted data independently from the enrolled studies, and the odds ratios (OR) or the standardized mean difference (SMD) was utilized to identify and describe the prognostic factors for mortality.ResultsEight studies encompassing 251 patients with SLE-associated DAH were included in the meta-analysis. No significant publication bias was shown. Age at the diagnosis of DAH (SMD = 0.35, 95% confidence interval (CI) (0.08, 0.61), P = 0.01, I2 = 0.0%) was found to be an independent risk factor of mortality. Longer lupus disease duration (SMD = 0.28, 95% CI (0.01, 0.55), P = 0.042, I2 = 0.0%), concurrent infection (OR = 2.77, 95% CI (1.55, 4.95), P = 0.001, I2 = 37.5%), plasmapheresis treatment (OR = 1.96, 95% CI (1.04, 3.70), P = 0.038, I2 = 14.6%), and mechanical ventilation (OR = 6.11, 95% CI (3.27, 11.39), P < 0.0001, I2 = 23.3%) were also related to poor survival, whereas no noticeable relationships were revealed between survival and concurrent lupus nephritis (OR = 5.45, 95% CI (0.52, 56.95), P = 0.16, I2 = 58.4%) or treatment of cyclophosphamide (CTX) (OR = 0.74, 95% CI (0.16, 3.41), P = 0.70, I2 = 75.5%).ConclusionsOlder age at the diagnosis of DAH, longer disease duration of SLE, concurrent infection, plasmapheresis treatment, and mechanical ventilation were found related to increased mortality in patients with SLE-associated DAH according to our meta-analysis. However, due to limited studies with heterogeneity, these results should be interpreted cautiously. Notably, severe diseases rendered the requirement of plasmapheresis treatment and mechanical ventilation are themselves associated with poor outcome. Randomized trials of therapeutics are needed to determine the most efficacious strategies for SLE-associated DAH for better management of this life-threatening complication.

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Dataset Information

Long noncoding RNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in alveolar hemorrhage associated with systemic lupus erythematosus.

Background

Methods

Results

Conclusions

Publications

Long noncoding RNA SNHG16 regulates TLR4-mediated autophagy and NETosis formation in alveolar hemorrhage associated with systemic lupus erythematosus.

Similar Datasets

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