Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a devastating multisystemic autoimmune disorder. However, the molecular mechanisms underlying its pathogenesis remain elusive. Some patients with Noonan syndrome, a congenital disorder predominantly caused by gain-of-function mutations in the protein tyrosine phosphatase SH2 domain-containing PTP (SHP2), have been shown to develop SLE, suggesting a functional correlation between phosphatase activity and systemic autoimmunity. To test this directly, we measured SHP2 activity in spleen lysates isolated from lupus-prone MRL/lpr mice and found it was markedly increased compared with that in control mice. Similar increases in SHP2 activity were seen in peripheral blood mononuclear cells isolated from lupus patients relative to healthy patients. To determine whether SHP2 alters autoimmunity and related immunopathology, we treated MRL/lpr mice with an SHP2 inhibitor and found increased life span, suppressed crescentic glomerulonephritis, reduced spleen size, and diminished skin lesions. SHP2 inhibition also reduced numbers of double-negative T cells, normalized ERK/MAPK signaling, and decreased production of IFN-γ and IL-17A/F, 2 cytokines involved in SLE-associated organ damage. Moreover, in cultured human lupus T cells, SHP2 inhibition reduced proliferation and decreased production of IFN-γ and IL-17A/F, further implicating SHP2 in lupus-associated immunopathology. Taken together, these data identify SHP2 as a critical regulator of SLE pathogenesis and suggest targeting of its activity as a potent treatment for lupus patients.

The phenolic fraction of extra virgin olive oil modulates the activation and the inflammatory response of T cells from patients with systemic lupus erythematosus and healthy donors

“…In addition, PE acts as a key positive regulator of ERK1/2 phosphorylation, decreasing PHA‐induced phosphorylation. On the contrary, previous studies have shown that ERK signaling pathway is decreased in T cells from SLE patients, been associated with overactivation of T cells . Our data did not shown this expected decreased expression of ERK pathway, but similar results between patients with SLE and healthy donors, but these discrepancies might be due to the inactive condition of the cohort of patients along with their pharmacological treatment.…”

Growth Factor Midkine Promotes T-Cell Activation through Nuclear Factor of Activated T Cells Signaling and Th1 Cell Differentiation in Lupus Nephritis

“…21,22 Inhibition of SH2 domain-containing protein tyrosine phosphatase reduces the proliferation of CD4 À CD8 À T cells and decreases the production of IFN-g and IL-17A in lupusprone MRL/lpr mice. 37 In the present study, MK did not affect numbers of CD4 À CD8 À T cells and the production of these cytokines. Dysfunction of Tregs leads to the exacerbation of LN, with a reduction in IL-2 transcription in TMPD-induced LN and in lupus-prone MRL/lpr mice.…”

Transancestral mapping and genetic load in systemic lupus erythematosus

“…Of the 147,111 Immunochip SNPs that passed quality control analyses, only 30% begin or end a CpG site. Although this is a novel SLE association, GRB2 reportedly regulates SHP2 activity2728, a potential contributor to SLE pathogenesis29.…”