Biology subjects

Tumurkhuu, G.

Publications and source records attributed to Tumurkhuu, G..

3 recordsLinked to original sources

bioRxiv2024

Loss of TRIM21 drives UVB-induced systemic inflammation by regulating DNA-sensing pathways

BackgroundExposure of systemic lupus erythematosus (SLE) patients to ultraviolet light B (UVB) triggers local and systemic inflammation, with cytosolic DNA sensing and induction of type I interferons (IFNs) known to play a role. We previously identified TRIM21 as a negative regulator of DNA sensing and IFN expression. Here we explore the role of TRIM21 in regulating local and systemic responses following UVB exposure. MethodsWT (C57BL/6) and Trim21-/- mice were irradiated with UVB (100mJ/cm2) daily for 1 and 3 weeks, and UVB-induced inflammation in skin, blood, and spleen were analyzed by qPCR, histology, RNA sequencing and flow cytometry. Mechanistic studies were performed in bone marrow-derived macrophages (BMDMs) and mouse skin fibroblasts (MDF) from WT and Trim21-/- mice, and TRIM21-/-THP-1 cells. ResultsInfiltration of inflammatory cells and induction of type I IFN developed in UVB-exposed areas in both sets of mice, however Trim21-/-mice developed splenomegaly, enhanced total IgG levels and IFN-stimulated genes (ISG) in the blood and spleen. Enhanced basal and UVB-dependent Ifnb1 expression was observed in Trim21-/- BMDMs and MDFs, which was dependent on the cytosolic DNA sensing cGAS-STING pathway. Mechanistically, we found both degradation of DDX41 and STING levels were impaired in stimulated Trim21-/-BMDMs. ConclusionTaken together, our results indicate that TRIM21 protects against IFN induction at local and systemic levels through restricting STING signaling. Our finding that reduced levels of TRIM21 are observed in SLE patients with cutaneous involvement indicates a potential role for TRIM21 in guarding against systemic flare in SLE patients.

immunology↗

bioRxiv2024

Alterations in genes associated with cytosolic RNA sensing in whole blood are associated with coronary microvascular disease in SLE

ObjectiveTo investigate whether gene signatures discriminate systemic lupus erythematosus (SLE) patients with coronary microvascular dysfunction (CMD) from those without and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD. MethodsThis study collected whole blood RNA samples from female subjects aged 37 to 57, comprising 11 SLE patients (4 SLE-CMD, 7 SLE-non-CMD) and 10 HC. Total RNA was then used for library preparation and sequencing. Differential gene expression analysis was performed to identify gene signatures associated with CMD in SLE patients using DEseq2 v1.42.0. Gene Set Enrichment Analysis were performed by ClusterProfiler v4.10.0 and pathfindR v2.3.1. ResultsRNA-seq analysis revealed 143 differentially expressed (DE) genes between the SLE and HC groups. GO analysis indicated associations with virus defense and interferon signaling in SLE. 14 DE genes were identified from comparison between SLE-CMD and SLE-non-CMD with adjusted parameters (padj < 0.1). Notably, SLE-CMD exhibited elevated levels of genes associated with RNA sensing, while downregulated genes in SLE-non-CMD were associated with blood coagulation and cell-cell junction. Further investigation highlighted differences in IFN signaling and ADP-ribosylation pathways between SLE-CMD and SLE-non-CMD, suggesting distinct molecular mechanisms underlying vascular changes in CMD and reduced left ventricular function in non-CMD. ConclusionOur study identified a unique gene signature in SLE-CMD compared to the HC group, highlighting the significant involvement of type 1 interferon, RIG-I family proteins, and chronic inflammation in the progression of SLE-CMD. The intricate relationship between SLE-CMD and these factors underscores their probable role in initiating and advancing SLE-CMD.

bioinformatics↗

bioRxiv2021

Neutrophils contribute to ER stress in lung epithelial cells in the pristane-induced diffuse alveolar hemorrhage mouse model

Diffuse alveolar hemorrhage (DAH), although rare, is a life-threatening complication of systemic lupus erythematosus (SLE). Little is known about the pathophysiology of DAH in humans, although increasingly neutrophils, NETosis and inflammatory monocytes have been shown to play an important role in the pristane-induced model of SLE which develops lung hemorrhage and recapitulates many of the pathologic features of human DAH. Using this experimental model, we asked whether endoplasmic reticulum (ER) stress played a role in driving the pathology of pulmonary hemorrhage and what role infiltrating neutrophils had in this process. Analysis of lung tissue from pristane-treated mice showed genes associated with ER stress and NETosis were increased in a time-dependent manner and reflected the timing of CD11b+Ly6G+ neutrophil accumulation in the lung. Using precision cut lung slices from untreated mice we observed that neutrophils isolated from the peritoneal cavity of pristane-treated mice could directly induce the expression of genes associated with ER stress, namely Chop and Bip. Mice which had myeloid-specific deletion of PAD4 were generated and treated with pristane to assess the involvement of PAD4 and PAD4-dependent NET formation in pristane-induced lung inflammation. Specific deletion of PAD4 in myeloid cells resulted in decreased expression of ER stress genes in the pristane model, with accompanying reduction in IFN-driven genes and pathology. Lastly, coculture experiments of human neutrophils and human lung epithelial cell line (BEAS-2b) showed neutrophils from SLE patients induced significantly more ER stress and interferon-stimulated genes in epithelial cells compared to healthy control neutrophils. These results support a pathogenic role of neutrophils and NETs in lung injury during pristane-induced DAH through the induction of ER stress response and suggest that overactivation of neutrophils in SLE and NETosis may underlie development of DAH.

immunology↗