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.

Eligibility Criteria:
Inclusion Criteria:

* SLE diagnosed patients between (18- 60) years old will be enrolled.

Exclusion Criteria:

* Patients with known pre-existing immunological disorders.
* Patients with known pre-existing infection.
* clinical diagnosis of cancer.
* patients diagnosed with concomitant acute myocardial infarction.