Elucidating the Functional Mechanisms by Which the Protein Tyrosine Phosphatase SHP2 Is Involved in the Pathogenesis of Systemic Lupus Erythematosus
Abstract
Systemic lupus erythematosus (lupus) is a devastating disorder that causes widespread inflammation. However, the how or why one develops lupus remains largely unknown. Current therapy involves anti-inflammatory and immunosuppressive drugs, but these tend to be rather non-specific and their extended use can lead to bad side effects. Therefore, the need to develop novel, more targeted therapies for lupus is critical. Recently, over 50 patients with Noonan Syndrome (NS), a genetic disorder caused by activating mutations in a specific enzyme called SHP2, also developed lupus, suggesting a possible link between this increased enzyme activity and lupus disease onset. To test this, we measured SHP2 activity in spleen cells isolated from lupus-prone mice, both before (8-week old) and during (16-week old) active disease. We found that the activity of SHP2 was highly increased at both time points. Moreover, SHP2 activity was increased in peripheral blood mononuclear cells (PBMCs) isolated from lupus patients, suggesting enhanced SHP2 activity in patients as well. SHP2 is a key regulator of nearly all cellular signaling pathways that control growth and survival. To assess whether SHP2 plays a role lupus-specific signaling pathways, we used an inhibitor for its activity (11a-1) and found that lupus mice and lupus patient T cells treated with the inhibitor both showed reduced T cell growth and decreased production of at least two cytokines, interferon gamma (IFN gamma) and interleukin 17A/F (IL17A/F). Importantly, reducing SHP2 activity in the lupus mice also increased lifespan, improved glomerulonephritis, decreased spleen size, and reduced skin lesions, confirming SHP2’s involvement in lupus. However, the specific mechanisms for how increased SHP2 activity affects T cell activity remains unclear. Therefore, in this lupus impact award proposal, we will highlight two areas of encouragement: (1) understanding lupus disease mechanisms and (2) determining pathobiology of lupus in specific target tissues. We hypothesize that that SHP2 is involved in the development and/or onset of lupus, likely through its ability to regulate immune responses on cytokine and inhibitory receptor signaling pathways. Given our strong preliminary results suggesting that SHP2 plays a key role in the development and/or progression of lupus, we believe it may serve an attractive novel drug target for treatment of this disease in patients. We propose these Specific Aims: Aim 1: To determine SHP2-dependent effects on signaling in cells and to identify cytokine subsets abnormally regulated in lupus-prone mice. SHP2 activity is elevated in cells from tissues of lupus mice. Moreover, T cells isolated from lupus mice treated with the SHP2 inhibitor have decreased growth and production of at least two cytokines, INF gamma and IL17A/F, suggesting SHP2 plays an active role in lupus disease. However, the mechanisms by which this occurs remain unclear. Here, using lupus mouse models, we will examine the effects of SHP2 activity and their signaling targets in cells from kidney, spleen, thymus, as well as in PBMCs and immune cell subsets, to identify the SHP2 functions in lupus. Cytokine profile analyses from serum, immune-cell subsets, and tissue from the various lupus mice will also be conducted. Aim 2: To determine the SHP2-dependent effects on signaling in cells and to identify cytokine subsets affected in human lupus. Our preliminary data demonstrate that SHP2 activity is increased in PBMCs isolated from lupus patients. To assess whether SHP2 activity is abnormal in human lupus, we will determine the total protein, mRNA, and activity levels of SHP2 from serum and PBMCs isolated from disease active lupus patients, as well as from normal subjects. Signaling proteins of SHP2 will be measured in PBMCs and immune cell subsets isolated from these patients to determine SHP2 activity effects in lupus. Finally, we will conduct a cytokine analysis profile in lupus patient samp
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110784
Entities
People
- Maria Kontaridis
Organizations
- United States Army