Tumor necrosis factor-a (TNF), a proinflammatory cytokine, functions by activating two cell surface receptors, TNFR1 and TNFR2. Current commercially approved anti-TNF therapies neutralize TNF thus preventing both TNFR1 and TNFR2 activation. Although these anti-TNF agents have demonstrated great efficacy in treating immune-mediated diseases, including psoriasis and psoriatic arthritis, potentially life-threatening infections and malignancies are associated with long-term use. Preclinical studies showed these unintended effects are due to TNFR1, not TNFR2 inactivation. Further, a subset of patients do not adequately respond to anti-TNF therapy over time. Unfortunately, no clinical test to predict responsiveness to the anti-TNF therapy is available. Our long-term goal is to demonstrate that selective inactivation of TNFR2 pathways with chemical inhibitors is effective in treating immune-mediated diseases with reduced adverse effects. Secondly, our studies may link a genetic variant of TNFR2 (TNFR2-M196R) to the reduced responsiveness to anti-TNF drugs. Our preliminary results show global knockout of TNFR2 is sufficient to inhibit psoriatic inflammation in a mouse model. Thus, selectively blocking TNFR2 pathways may ameliorate psoriasis and potentially reduce TNFR1 inhibition-related adverse events. Previously we and others, demonstrated that PRMT5 (protein arginine methyltransferase 5)-mediated arginine dimethylation on specific transcription factors is critical for TNF-mediated inflammatory gene induction. Our recent results show that PRMT5 activation is downstream of TNFR2, not TNFR1, and that a PRMT5-specific chemical inhibitor, EPZ015666 (EPZ), reduces psoriatic inflammation in mice. Earlier, we also demonstrated that non-muscle myosin (myosin) is an ?off-switch? of TNFR2 signaling by binding to its cytosolic signaling domain. We now discovered that unlike TNFR2, TNFR2-M196R fails to bind to myosin in cultured cells or in cells isolated from human blood and show constitutive proinflammatory activity in vitro. Based on our findings and preliminary data we hypothesize that inactivation of TNFR2 or chemical inhibition of PRMT5 will ameliorate psoriatic inflammation. Further, a defect in myosin binding to the TNFR2 genetic variant, TNFR2-M196R, causes a constitutive, TNF-independent activity, thus leading to reduced responsiveness in patients treated with anti-TNF agents. We will test this hypothesis in two aims.
In Aim 1, using two psoriasis mouse models, we will investigate the mechanisms underlying TNFR2 activity on psoriatic pathogenesis. We will also study the mechanistic basis of the constitutive activities of TNFR2-M196R in cultured cells. Furthermore, will test retrospectively if this polymorphism would predict responsiveness to anti-TNF agents in patients with psoriatic diseases.
In Aim 2, using in vitro approaches we will investigate the mechanistic role of PRMT5 post-translational modifications on TNFR2 function. Further, using chemical and genetic approaches we will test the effect of PRMT5 inhibition on psoriasis pathogenesis. Our approach, blocking TNFR2 signaling and leaving TNFR1 activity intact, is novel and may lead to improved safety for the long-term treatment of chronic immune-mediated diseases. Further, our study may help to predict inadequate responders to anti-TNF therapies early on, allowing more personalized approach in treating psoriatic diseases.

Public Health Relevance

Anti-TNF biological agents have been successfully used to treat psoriatic diseases, however, these medications are associated with potentially life-threatening side effects including development of serious infections or cancer. Furthermore, a subset of patients does not adequately respond to anti- TNF therapy over time. In this application, we propose to identify novel drug targets of psoriatic diseases that will have fewer adverse effects and also to identify specific genetic markers that may help to predict inadequate responders of anti-TNF therapies, early on.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Cibotti, Ricardo
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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