Deconstructing the molecular and cellular mechanisms of psoriatic arthritis pain by an improved animal model

About This Grant

Abstract Psoriasis (Ps) is an autoimmune-mediated systemic inflammatory skin disease. Approximately one-third of Ps patients eventually develop psoriatic arthritis (PsA). PsA is one of the most common forms of arthritis, impacting around 1 million individuals in the US. Mechanical pain associated with PsA in joints and skin, triggered by joint loading, movement, and skin touch, is a leading cause of hospitalization for patients and represents a serious unmet medical need. Current PsA therapeutics, including recently developed interleukin 17 (IL17), interleukin 23 (IL23), and Janus kinase (JAK) inhibitors, only offer partial relief from pain. Furthermore, these treatments prove ineffective for some individuals and have side effects. Therefore, there exists a pressing need to identify new targets for PsA pain. Animal pain models can facilitate the rational discovery of novel analgesics. Although current animal models of PsA have advanced our understanding of PsA pathogenesis, it is unknown if they can be used for studying PsA pain because pain has not been characterized in any of these models. Importantly, most of them have limitations that hinder their use for studying chronic PsA pain. We propose to improve, characterize, and validate a mouse mannan model for PsA pain (Aim. 1). Due to the lack of animal models, we know little about the mechanisms underlying PsA pain. Emerging evidence demonstrated that the systemic and local tissue levels of lysophosphatidylcholine (LPC), a proinflammatory mediator and the most abundant systemic phospholipid in humans, are elevated in psoriatic patients, suggesting its potential involvement in the pathogenesis of PsA pain. Using our improved and validated mouse model in Aim 1, we will examine whether elevated LPC contributes to PsA pain (Aim 2). Our previous work and preliminary data demonstrated that LPC can activate primary sensory neurons, joint chondrocytes, and skin keratinocytes via a mechanosensitive ion channel TRPV4. These findings prompted us to ask whether LPC drives PsA joint and cutaneous pain via TRPV4 in sensory neurons, chondrocytes, and keratinocytes (Aim 3). Success completion of this project will lead to the development of the first animal model of PsA pain that can be used to substantively advance our understanding of PsA pain mechanisms. In addition, this project will pave the way to identify LPC and TRPV4 as mechanistic therapeutic targets with exciting potential to mitigate PsA pain.