# P2X7 Receptor Splice Variants in Psoriasis Pathophysiology

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $206,580

## Abstract

Psoriasis is a cutaneous autoimmune disease that affects as many as 125 million people worldwide. Current
therapeutics for psoriasis include systemic acting immuno-suppressive drugs for which long-term adverse
effects remain a concern. Thus, a better understanding of psoriasis pathophysiology and cutaneous
inflammation is pivotal for the development of new therapeutics. There are approximately 9000 alternatively
spliced variants differentially expressed in psoriasis. However, pathways that lead to alternatively spliced
isoforms remain to be identified in psoriasis patients. In this regard, the alternatively spliced purinergic P2X7
receptor variant B (P2X7RB) is highly expressed in human psoriatic lesions; whereas the canonical P2X7R
variant A (P2X7RA) is expressed comparably in lesional, non-lesional, and normal human skin. Extracellular
ATP, an alarmin, signaling through the P2X7R is a particularly appealing therapeutic pathway. P2X7RA
stimulation leads to inflammasome and NF-κB activation and induction of the IL-23/IL-17 axis, which are
psoriasis susceptibility pathways. Thus, upstream P2X7R signaling links early inflammatory triggers with
psoriasis susceptibility factors. In fact, results from our ongoing studies have revealed that signaling through
the P2X7RA leads to the development of psoriatic dermatitis in multiple murine and human models of
psoriasis; however this is only an acute response that resolves within 6 days. Conversely, the P2X7RB variant
lacks the intracellular C-terminus that confers P2X7R signaling cytotoxicity and therefore we hypothesize limits
the ability of P2X7R signaling to induce inflammatory resolution. Signaling via the P2X7RB enhances cellular
proliferation, decreases ATP-induced apoptosis, and in heterotrimers with P2X7RA, P2X7RB potentiates
inflammatory responses. To understand the role of these variants in psoriasis pathophysiology, it will be
necessary to determine which variants are crucial for the induction and maintenance of psoriasis. Our central
hypothesis is that cutaneous overexpression of the P2X7RB variant has a prominent role in the
pathophysiology of psoriasis. The overarching goal of this proposal is to establish the mechanisms that induce
P2X7RB overexpression and to understand the involvement of P2X7RB signaling in psoriasis. To this end, we
have developed the following specific aims: Aim 1: Establish the alternative splicing pathways that lead to
P2X7RB variant expression and Aim 2: Determine the role of P2X7RB in psoriasis pathogenesis.
P2X7RA is an early upstream mediator of many biological and immunological pathways, whose blockade could
be an immunological disaster. Importantly, our findings herein, will be exploited for novel psoriasis therapies by
precisely targeting only the alternative splicing pathways leading to the overexpression of P2X7RB, while
retaining canonical P2X7RA and the patient immunologically active.

## Key facts

- **NIH application ID:** 10107014
- **Project number:** 1R21AR078349-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ALICIA R MATHERS
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $206,580
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107014

## Citation

> US National Institutes of Health, RePORTER application 10107014, P2X7 Receptor Splice Variants in Psoriasis Pathophysiology (1R21AR078349-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10107014. Licensed CC0.

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