Leptin and Neutrophil‐Activating Peptide 2 Promote Mesenchymal Stem Cell Senescence Through Activation of the Phosphatidylinositol 3‐Kinase/Akt Pathway in Patients With Systemic Lupus Erythematosus

Abstract

Objective. Mesenchymal stem cells (MSCs) derived from patients with systemic lupus erythematosus (SLE) exhibit enhanced senescence. Cellular senescence has been reported to be induced by several inflammatory cytokines, including interferon-a (IFNa) and IFNg, that are involved in the pathogenesis of SLE. We undertook this study to investigate whether the inflammatory environment in SLE could affect MSC senescence.Methods. Cellular senescence was measured by staining of senescence-associated b-galactosidase and by expression of the cell cycle inhibitors p53 and p21. Eighty cytokines and chemokines in serum from healthy controls and patients with SLE were identified by cytokine antibody array.Results. SLE serum promoted senescence of MSCs, which was reversed by the phosphatidylinositol 3-kinase (PI3K)/Akt signaling inhibitor LY294002 but not by the JAK/STAT inhibitor AG490 and not by the MEK/ERK inhibitor PD98059. Cytokine antibody array analysis revealed that leptin and neutrophil-activating peptide 2 (NAP-2) were the 2 factors most significantly elevated in SLE serum compared with normal serum. Blockade of leptin or NAP-2 in MSC cultures abolished SLE seruminduced senescence, while direct addition of these 2 factors could promote senescence in cultures of normal MSCs. Inhibition of PI3K/Akt signaling with LY294002 reduced leptin-and NAP-2-induced senescence in MSCs.Conclusion. Taken together, our data show that leptin and NAP-2 act synergistically to promote MSC senescence through enhancement of the PI3K/Akt signaling pathway in SLE patients.

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases

“…Accordingly, pharmacological blockade of PI3Kγ with AS605240 blocks T-cell activation, autoantibody production, renal infiltration and TNF release by macrophages, and ameliorates glomerulonephritis, thus extending lifespan in mouse models of lupus 181,183 . Additionally, the broad PI3K inhibitor LY294002 improves the survival of mesenchymal stem cells (MSCs), which exhibit enhanced senescence in patients with SLE 184 . PI3Kδ is highly expressed in the synovium and cultured FLS of patients with RA 185 , and its expression is selectively induced over other PI3K isoforms by TNF.…”

The Complex Role of Leptin in SLE: Is Leptin A Key Link between Metabolic Syndrome, Accelerated Atherosclerosis and Autoimmunity?

“…Leptin and Neutrophil-Activating Peptide 2 act synergistically to promote mesenchymal stem cells senescence through enhancement of the PI3K/Akt signaling pathway in SLE patients. [30] Table 1: In the table we summarized studies concerning circulating leptin levels in human SLE. In the second part of the table we reported the evidences of leptin involvement in autoimmune processes.…”

CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms

“…In the past decade, mesenchymal stem cells (MSCs) have emerged as a promising new therapy for the treatment of SLE7. MSCs are adult stem cells isolated from various human tissues including bone marrow, adipose tissue, umbilical cord blood, and skeletal muscle; MSCs can differentiate into various cell types and can potentially replace damaged cells in vivo 489.…”