Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
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.
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 mice
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.
1 Chandrasekharan, U. et al. Blood 109, p1944, 2007
2 Retser, E. et al. Arthr & rheum 65, p2300, 2013
To cite this abstract in AMA style:Chandrasekharan U, Braley C, Harvey J, Wang Z, DiCorleto P, Husni ME. Selective Inhibition of Tumor Necrosis Factor-α Receptor 2 (TNFR2) Activity Alleviates Psoriasiform Inflammation in Mouse Models [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/selective-inhibition-of-tumor-necrosis-factor-%ce%b1-receptor-2-tnfr2-activity-alleviates-psoriasiform-inflammation-in-mouse-models/. Accessed November 28, 2021.
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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/