Systems biology of lupus: mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment

Abstract

Systemic lupus erythematosus (SLE) is characterized by the dysfunction of T cells, B cells, and dendritic cells, the release of pro-inflammatory nuclear materials from necrotic cells, and the formation of antinuclear antibodies (ANA) and immune complexes of ANA with DNA, RNA, and nuclear proteins. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key factor in abnormal activation of T and B cells in SLE. In T cells, increased production of nitric oxide and mitochondrial hyperpolarization (MHP) were identified as metabolic checkpoints upstream of mTOR activation. mTOR controls the expression T-cell receptor-associated signaling proteins CD4 and CD3zeta through increased expression of the endosome recycling regulator Rab5 and HRES-1/Rab4 genes, enhances Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B cells, and blocks the expression of Foxp3 and the generation of regulatory T cells. MHP, increased activity of mTOR, Rab GTPases, and Syk kinases, and enhanced Ca2+ flux have emerged as common T and B cell biomarkers and targets for treatment in SLE.

Figure 1

Schematic outline of the metabolic pathways controlling (PPP, GSH, and NO) and sensing (mTOR) MHP in lupus T cells. In normal T cells, MHP and mitochondrial biogenesis is mediated via production of NO by eNOS or nNOS [140] and up-regulation of transcription factors PGC-1α, Tfam, and ALAS [147]. NO production by eNOS may be compartmentalized to the T cell synapse [117]. NO causes transient MHP via reversible inhibition of complex IV/cytochrome c oxidase [148] and persistent MHP via S-nitrosylation of complex I of the ETC in a state of GSH depletion [113]. The PPP regulates the Δψ_m by producing (1) NADPH that serves as a reducing equivalent for GSH regeneration from its oxidized form GSSG and for the production of NO by NOS and (2) ribose 5-phosphate for biosynthesis of nucleotides, ADP, ATP, NAD, NAADP, (c)ADP-ribose, and cGMP, the latter is a second messenger of NO. NAADP and (c) ADP-ribose induce Ca²⁺ release from the ER via ryanodine receptors (RyR). mTOR senses Δψ_m and regulates IP3R-mediated Ca²⁺ release [62]. The intracellular rapamycin receptor FKBP12 directly binds the RyR. The Bcl-2 family proteins control permeability of the outer mitochondrial membrane and release of apoptosis-inducing factors. Necrosis-prone T cells release oxidized DNA and HMGB1 which stimulate B cells, macrophages, and DCs. In turn, B cells produce IL-10 and macrophages and DCs produce NO which stimulate MHP of T cells.

Figure 2

Schematic cascade of signaling pathways controlling MHP and enhanced receptor recycling in lupus T cells. Broken line demarcates checkpoints affected by rapamycin.