Role for SHP2 as a therapeutic target for systemic lupus erythematosus
Abstract
Systemic lupus erythematosus (SLE) is a devastating autoimmune disorder characterized by widespread inflammation affecting multiple tissues. However, the molecular mechanisms in SLE, and the identification of specific and targeted therapies, remain largely unknown. Our lab has been interested in studying the biological effects of the protein tyrosine phosphatase SHP2. Because a major role for SHP2 is to serve as a positive transducer of inflammatory responses via cytokine-mediated signaling, we hypothesized that it may therefore play a critical role in autoimmunity and/or onset of disease. Therefore, to initially determine whether there is a role for SHP2 in SLE, we collected human peripheral blood mononuclear cells from SLE disease active patients as well as from normal patients as a control. We found SHP2 activity was significantly increased in the SLE patient cells, as compared to controls, implicating SHP2 directly in SLE pathogenesis. In addition, tissues isolated from female MRL/lpr (SLE-prone mice) also showed significantly elevated SHP2 phosphatase activity (8-fold), as compared to MRL/MpJ (MRL strain control) and C57/Bl6 wildtype (WT) control mice. To determine whether there was a role for SHP2 in mitigating the syndromic features of SLE, we conducted a pilot experiment using a newly synthesized, potent and specific inhibitor for SHP2. We showed that progression of SLE disease was substantially ameliorated in SLE mice after only 6 weeks of treatment with the inhibitor. Importantly, no adverse effects of treatment with the drug were observed. Histologically, the inhibitor prevented the progression of both the crescentic glomerulonephritis and the splenomegaly, which manifest as SLE disease progresses in MRL/lpr mice. These data suggest that normalization of SHP2 activity is required to prevent the progression of SLE disease. Mechanistically, we isolated and identified the specific immune cell population affected by increased SHP2 activity, as well as the molecular signaling pathways and effectors aberrantly regulating downstream signaling events. Together, these data identify, for the first time, a possible new, potent and more targeted therapy for treatment of patients with SLE.