Common fatty acid contributes to temperature and pain sensitivity in psoriasis plaques

A common fatty acid found in the Western diet breaks down into compounds that contribute to increased temperature and pain – but not itch – sensitivity in psoriatic lesions. The finding could lead to better understanding of how lipids communicate with sensory neurons, and potentially to improved pain and sensitivity treatments for psoriasis patients.

Linoleic acid is a fatty acid found in vegetable oils, nuts and seeds, and is one of the predominant fatty acids found in the Western diet. Metabolites from linoleic acid – the products formed when the body breaks it down through digestion – play a role in skin barrier function.

“We noticed high levels of two types of lipids derived from linoleic acid in psoriatic lesions,” says Santosh Mishra, associate professor of neuroscience at North Carolina State University and corresponding author of the research. “That led us to wonder whether the lipids might affect how sensory neurons in these lesions communicate. We decided to investigate whether their presence could be related to the temperature or pain hypersensitivity that many psoriasis patients report.”

The research team used mass spectrometry to create lipid profiles of skin from psoriatic lesions. They focused on two types of linoleic acid-derived lipids, or oxylipids: 13-hydroxy-9,10-epoxy octadecenoate (9,13-EHL) and 9,10,13-trihydroxy-octadecenoate (9,10,13-THL). The first form, 9,13-EHL, can convert into the more stable 9,10,13-THL form via interaction with certain enzymes.

The researchers found that while both forms bind to receptors on sensory neurons within the skin, the more stable form – 9,10,13-THL – had a longer lasting effect than 9,13-EHL.

They also found that once the lipids bind to the neuronal receptor, they activate the neurons expressing TRPA1 and TRPV1 receptors that are involved in temperature and pain hypersensitivity, opening communications channels to the central nervous system.

Interestingly, the lipids did not have any effect on itch.

“It was surprising that these lipids could create hypersensitivity but not impact itch sensation, which is usually the most troublesome symptom associated with psoriasis,” Mishra says. “This most likely has to do with how the neuron is activated – a mechanism we still haven’t uncovered.”

Now that an association between linoleic acid and hypersensitivity to temperature and pain has been established, the researchers want to further explore exactly how this response is being created. They hope that the answers may lead to solutions that can relieve these symptoms in psoriasis patients.

“We know that this lipid moves from one form to another, but don’t yet know what causes that,” Mishra says. “We also know what protein the lipids are binding to, but not where the bond occurs. Answering these questions may hopefully lead to new therapies – or dietary solutions – for some psoriasis sufferers.”

The work appears in JID Innovations, and is supported by the National Institute on Aging and the National Institutes of Health. Josh Wheeler, a postdoctoral researcher at NC State, is first author.

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Note to editors: An abstract follows.

“Endogenous Derivatives of Linoleic Acid and Their Stable Analogues are Potential Pain Mediators”

DOI: 10.1016/j.xjidi.2022.100177

Authors: Joshua J. Wheeler, Santosh Mishra, North Carolina State University; Anthony F. Domenicheillo, Jennifer R Jensen, Gregory S. Keyes, Kristen M. Maiden, Christopher E. Ramsden, National Insitutes of Health; John M. Davis, University of Illinois at Chicago
Published: Dec. 25, 2022 in JID Innovations

Abstract:
Psoriasis is characterized by intense pruritus, with a subset of psoriatic individuals experiencing thermal hypersensitivity. However, the pathophysiology of thermal hypersensitivity in psoriasis and other skin conditions remains enigmatic. Linoleic acid (LA) is an omega-6 fatty acid that is concentrated in the skin, and oxidation of LA into metabolites with multiple hydroxyl and epoxide functional groups has been demonstrated to play a role in skin barrier function. Previously, we identified several LA-derived mediators that were more concentrated in psoriatic lesions, but the role of these lipids in psoriasis remains unknown. Here, we report that two such compounds 9,10-epoxy-13-hydroxy-octadecenoate (9,13-EHL) and 9,10,13-trihydroxy-octadecenoate (9,10,13-THL) are present as free fatty acids and induce nociceptive behavior in mice but not rats. Chemically stabilizing 9,13-EHL and 9,10,13-THL, through the addition of methyl groups, we observed pain and hypersensitization in mice. The nociceptive responses suggest an involvement of the TRPA1 channel, while hypersensitive responses induced by these mediators may require both TRPA1 and TRPV1 channels. Furthermore, we showed that 9,10,13-THL-induced calcium transients in sensory neurons are mediated through the Gβγ subunit of an unidentified GPCR. Overall, mechanistic insights from this study will guide the development of potential therapeutic targets for the treatment of pain and hypersensitivity.