SLE Clinical Trial
Official title:
Studying of New Signaling Pathway Targeting Systemic Lupus Erythematosus
Systemic lupus erythematosus is inflammatory autoimmune disease that affects over one million people in the United States. It has a higher prevalence and incidence rate among women compared with men, and among African Americans compared with Caucasians. Despite advances in treatment, standardized mortality rates in SLE remain three times higher than in the general population. The risk of mortality is significantly increased because of renal disease, cardiovascular disease, and infection.The etiology of SLE is multifactorial, with genetic predisposition, environmental factors and epigenetic alterations are involved. However, the molecular mechanisms underlying this systemic autoimmune response remain largely unknown. A key issue in the pathogenesis of lupus is how intracellular antigens become exposed and targeted by the immune system.
Antinuclear antibodies play a direct role in pathogenesis by forming immune complexes. These
complexes can either deposit in the kidney or stimulate cytokine production. Dead and dying
cells can fill the blood with a plentiful supply of immune complex components in lupus. So
cell death is a critical issue in the pathway to auto-reactivity. Pyroptosis is a new member
of cell death list. It combines the release of pro-inflammatory mediators and nuclear
molecules in a way that could drive lupus. Nod-like receptor pyrins-3, caspase-1, IL-18, and
IL-1β are commonly accepted markers of pyroptosis.
Gasdermin D was recently identified as the final pyroptosis executioner downstream of
inflammasome activation, and may be an attractive drug target for many diseases. GSDMD is a
member of the gasdermin protein family. It was identified as a caspase substrate. Under
normal cellular conditions, the C-terminus of GSDMD auto-inhibits the pore-forming activity
of the N-terminus. When extracellular signals associated with pyroptosis activate
inflammasomes they subsequently cleave and activate caspases-1, -4, -5, and -11.
Consequently, activated caspase-1 cleaves and separates the N- and C-terminals of GSDMD.
Activated GSDMD forms nanoscopic pores in the cell membrane, leading to the release of
proinflammatory materials and cell swelling.
Reactive oxygen species regulates the signaling pathways in response to the changes of the
intracellular and extracellular environments. However, overproduction of ROS is toxic and
lead to dysfunction of cell and tissue. Oxidative stress is increased in SLE. The increased
ROS could promote the release of inflammatory related signaling factors, including nod-like
receptor inflammasome and nuclear factor-κB. A recent study showed that inhibition of ROS
generation suppressed pyroptosis of hematopoietic stem cells. It has been widely reported
that NF-kB is a critical molecular switch for cellular response to oxidative stress. NF-kB
exists in the form of dimer and has been demonstrated to be involved in the development and
progression of various diseases associated with inflammation, apoptosis, and proliferation. A
recent study showed that NF-kB is an essential transcription factor of GSDMD.
In the recent decades, increasing evidence have revealed the roles of epigenetic
dysregulation, including microRNA, in the pathogenesis of SLE. MiRNAs is a class of short
non-coding RNA approximately 21-25 nucleotides in length that plays important roles in many
cellular processes by regulating gene expression. MiRNAs make up a novel class of
post-transcriptional gene regulators By combining with the 3' noncoding region of target gene
mRNA inducing their degradation or impairing their translation.
MiR-379-5p is located at delta-like 1 homolog-deiodinase, iodothyronine 3 genomic region on
14q32.31. The DLK1-DIO3 region contains 54 miRNAs that is associated with organ development
and disease pathogenesis, especially carcinogenesis. Luciferase reporter assays showed that
GSDMD was a direct target of miR-379-5p. The over-expression of miR-379-5p blocked the
arsenite induced increases of GSDMD levels effect that were reversed by up-regulation of
GSDMD.
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