Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus
Jianxun Wang, … , Zhong-Yin Zhang, Maria I. Kontaridis
Jianxun Wang, … , Zhong-Yin Zhang, Maria I. Kontaridis
Published May 16, 2016
Citation Information: J Clin Invest. 2016;126(6):2077-2092. https://doi.org/10.1172/JCI87037.
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Research Article Autoimmunity

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.

Authors

Jianxun Wang, Masayuki Mizui, Li-Fan Zeng, Roderick Bronson, Michele Finnell, Cox Terhorst, Vasileios C. Kyttaris, George C. Tsokos, Zhong-Yin Zhang, Maria I. Kontaridis

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Figure 1

SHP2 activity is upregulated in both lupus patients and lupus-prone MRL/lpr mice, the normalization of which reverses aberrant ERK/MAPK signaling.

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SHP2 activity is upregulated in both lupus patients and lupus-prone MRL/...
(A) SHP2 immune complex PTP assays were conducted using pNPP as a substrate on human PBMC lysates and (B) mouse splenic lysates generated from 18-week-old control C57BL/6 WT, strain-control MRL/MpJ (MpJ), and lupus-prone MRL/lpr (lpr) female mice that were either vehicle or SHP2 inhibitor (11a-1) treated (7.5 mg/kg/d) for 6 weeks, starting at 12 weeks of age. Immunoblotting controls for levels of immunoprecipitated SHP2, showing comparable recovery, are shown below each figure. n = 6 human samples/group and n = 3–8 mice/group, respectively. Splenic lysates isolated from 18-week-old WT, MpJ, and MRL/lpr mice subjected to either vehicle or 11a-1 were immunoblotted with (C) anti–phospho-AKT and anti–phospho-p70S6K or (D) anti–phospho-ERK, as indicated, followed by anti-AKT, anti-p70S6K, and anti-ERK, respectively, to control for loading. Parallel experimental samples were blotted with anti-SHP2 or anti-GAPDH to determine expression levels of these proteins. Quantification of data (n = 3 mice/group) is shown to the right of each representative Western blot figure. Data represent mean ± SEM; *P < 0.05, 1-way or 2-way ANOVA with Holm-Sidak post-test when ANOVA was significant.