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Thesis/Dissertation
Date
2023-08
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Microbiology and Immunology
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http://dx.doi.org/10.34944/dspace/8944
Abstract
SLE is a chronic autoimmune disorder marked by immune dysregulation and inflammation. Multiple mitochondrial dysfunctions, such as increased mitochondrial reactive oxygen species (mROS), depolarized membrane potential, altered morphology, and changes in energy production, were observed in patients with systemic lupus erythematosus (SLE), suggesting that mitochondrial function plays a role in lupus pathogenesis. Calcium is an essential regulator of mitochondrial functions, and when macrophages become polarized, their metabolism is reprogrammed based on their phenotypes. The connection between mitochondrial calcium mobilization and lupus remains unclear. In this study, we explored the expression and function of the mitochondrial calcium uniporter (MCU) in monocytes/macrophages in lupus pathogenesis. We examined the ex vivo gene expression profiles of human renal biopsies with nephropathies, SLE whole blood, peripheral blood mononuclear cells (PBMCs), and mouse renal macrophages, identifying a decrease in MCU-related genes in Lupus nephritis and other inflammatory nephropathies. We also found that the expression of MCU-related genes significantly decreased in monocytes and macrophages stimulated with LPS and also upon M1/2 polarization, both from healthy controls and patients with SLE. Lastly, we generated hematopoietic and endothelial cell specific MCU knockout mice and used a pristane-induced lupus model to test in vivo the role of MCU in lupus development. Interestingly, there was no significant difference in disease severity between MCU knockout mice and wild-type mice, indicating that the absence of MCU did not improve nor worsen lupus pathology in mice. Since the LPS-induced down-regulation of MCU- related genes, found in human cells, was not consistently reproducible in murineiii
macrophages, these results suggest a species-specific regulation of MCU-related genes in innate immunity.
Macrophage plays a crucial role in both initiating and remitting inflammation. Imbalanced polarization of macrophage population has been identified in lupus patients. To understand the contribution of macrophage polarization in lupus, we conducted RNA sequencing on peripheral blood mononuclear cells (PBMCs) from healthy controls and SLE patients to assess gene expression changes related to macrophage polarization. Our findings reveal a differential regulation of 324 genes in SLE patients, primarily involved in inflammatory processes and type I interferon signaling, providing a molecular snapshot of the disease. Specifically, increased expression of M1 macrophage polarization associated genes was identified in SLE patients. Correlation analysis further elucidated the relationship between M1 polarization, lupus disease manifestations, complement activation, and disease activity, highlighting a robust interplay between these factors. Additionally, a strong correlation between the interferon-I signatures and M1 polarization was observed, indicating a profound interplay in SLE pathology.
In conclusion, these results provide valuable insights into the reduction of mitochondrial function during monocyte/macrophage activation and in lupus nephritis and pro-inflammatory orientation of peripheral blood monocytes. Although a causal link between MCU, macrophage polarization and lupus remain unclear, these results support further research to fully understand the complex relationship between mitochondrial function, calcium mobilization, macrophage polarization, and lupus pathogenesis.
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