Background/Purpose: Tumor necrosis factor-α (TNF) activates two receptors globally, TNFR1 and TNFR2. Neutralizing antibodies or soluble TNF receptors can inactivate TNF, blocking activity of both receptors, and have been successful in treating psoriasis (PsO) and psoriatic arthritis (PsA). However, continued use of anti-TNF therapy has been associated with an increase in serious infections, such as reactivation of tuberculosis and malignancies. These side effects are related to TNFR1 blockade. Using mouse models, we showed that activity of both TNFR1 and TNFR2 is critical for TNF-mediated inflammatory responses.¹ Recently, we identified that activation of PRMT5 (protein arginine methyltransferase 5), an enzyme critical for TNF-mediated inflammatory responses, is downstream of TNFR2 but not TNFR1 signaling. This makes PRMT5 a target for treating TNF-dependent inflammatory diseases. Our goal is to demonstrate that selective inactivation of TNFR2 via PRMT5 is effective in treating psoriatic diseases. Our objective is to determine the relative contributions of TNFR1 and TNFR2 to the development of PsO, and to test whether inhibition of PRMT5 activity will alleviate PsO and PsA in animal models.

Methods: To identify the role of TNF receptors in psoriasis we used the imiquimod (IMQ) mouse model. We applied IMQ (4 mg/day/mouse for 4 days) to 10-12 week old wild type (WT), TNFR1-null, TNFR2-null and TNFR1 & 2 double-null mice. To determine the role of PRMT5, we treated a specific PRMT5 small molecule inhibitor EPZ015666 topically 4 hours prior to IMQ application once a day for 4 days. Erythema, scaling and thickness of the IMQ or vehicle treated area was assessed by PASI (Psoriasis Area and Severity Index). Epidermal thickness was measured using ImagePro software on H&E stained skin sections. Immunohistochemistry was used to determine PRMT5 expression. Protein-incorporated SDMA (Symmetrical Dimethyl Arginine), which is the catalytic product of PRMT5 and works as a functional representation of PRMT5 activity, was measured in psoriatic skin using mass spectrometry. Further, we are currently testing whether EPZ015666 can inhibit PsA-like joint disease using a TNF overexpressing mouse strain (ihTNFtg mice²).

Results:  In WT mice, erythema, scaling, and thickness peaked at day 8 (PASI ~ 8.0). TNFR2-null or double-null mice skin inflammation was undetectable. TNFR1-null mice showed a PASI score of 1 – 2.5. H&E revealed significant keratinocyte hyperplasia and leukocyte infiltration in WT treated with IMQ, which were inhibited in TNFR2-null, TNFR1-null or double-null mice. Further, IMQ-treated mouse skin showed elevated PRMT5 expression. There was a ~ 2-fold increase of SDMA in mouse psoriatic skin compared to the adjacent normal skin. Importantly, topical application of PRMT5 inhibitor, EPZ015666, diminished the IMQ-induced PsO pathogenesis in WT mice (~ 75%).

Conclusion:  IMQ-induced psoriasis is critically dependent on TNFR2. An increase in the abundance of PRMT5 was also found in mouse psoriatic skin and the specific PRMT5 inhibitor that can block TNFR2 ameliorates psoriasis in mice.

References

1 Chandrasekharan, U. et al. Blood 109, p1944, 2007

2 Retser, E. et al. Arthr & rheum 65, p2300, 2013

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-inhibition-of-tumor-necrosis-factor-%ce%b1-receptor-2-tnfr2-activity-alleviates-psoriasiform-inflammation-in-mouse-models/