Pathophysiological role and plasticity of skin-projecting nociceptors in two major chronic skin disorders – NOMINATION
Differential role of nociceptors in the control of inflammation and prurit
Skin neurons, called nociceptors, do more than signal pain or itch: they directly communicate with immune cells and contribute to inflammation. We hypothesize that, depending on the inflammatory environment, these neurons retain a specific “imprint” that sustains the disease. Decoding this imprint could pave the way for innovative therapies.
The goal of the project was to define the diversity of responses of sensory neurons innervating the skin to cutaneous inflammation.
Our skin is much more than just a physical barrier. It is populated by many types of cells – structural, neural, and immune – that work together to detect external challenges (such as allergens or injuries) and respond appropriately. This complex system helps maintain the balance and health of the skin on a daily basis. However, when this balance is disrupted, it can lead to chronic inflammatory skin conditions. These affect a significant portion of the adult population and may manifest as redness, patches, persistent itching, or dryness. Each type of skin inflammation involves different biological mechanisms, particularly distinct immune responses driven by molecules called cytokines. Recent studies, including our own, have shed light on a less explored player in these conditions: the skin’s sensory nerves, especially those responsible for pain and itch (called nociceptors). These neurons do not merely transmit sensory signals; they can also actively contribute to inflammation by releasing substances that influence the immune response. To better understand this phenomenon, we have developed a new approach to study these sensory nerves at the cellular level. By combining advanced techniques in neuronal tracing, cell sorting, and single-cell genetic sequencing, we identified several subtypes of sensory nerves in the skin. Some of them appear particularly sensitive to chronic inflammatory environments. Our research project aims to: Better characterize these different types of sensory nerves in the skin, and understand how they adapt in an inflammatory context; Identify the substances released by these neurons, especially neuropeptides, that may influence skin inflammation; Test the functional role of these neurons by activating or silencing them in experimental models, to assess their direct impact on chronic inflammation. This work brings together expertise in neurobiology, dermatology, animal modeling, and computational analysis. By deepening our understanding of how sensory nerves interact with the skin’s immune system, we hope to uncover new therapeutic strategies for chronic inflammatory skin conditions.
We performed single-cell RNA analysis of skin-innervating neurons under both normal and pathological conditions. We then used pharmacological inhibitors of the receptor for an identified molecule, Alkal2, to demonstrate its role in the development of itch across multiple models of skin inflammation.
We also employed genetically modified mouse models to investigate the role of different immune cell populations in skin inflammation.
The work carried out in this project has provided new insights into how sensory nerves in the skin actively contribute to inflammation and chronic itch.
The first line of investigation focused on a neuronal signaling pathway involving the molecule Alk and its natural ligand Alkal2. In several models of allergic skin inflammation, researchers observed a marked increase in Alkal2 within sensory nerves located in the dorsal root ganglia. This overproduction activates Alk in spinal cord neurons, particularly in regions involved in transmitting itch signals.
To test the functional role of this pathway, researchers administered lorlatinib, an Alk inhibitor already used in oncology, to mice. The treatment significantly reduced scratching behaviors associated with skin inflammation, without altering visible signs of inflammation in the skin. Importantly, the inhibition had no effect in models of non-inflammatory acute itch, suggesting that the Alkal2-Alk pathway is specifically involved in chronic, inflammation-driven itch. These results indicate that blocking this pathway could be a promising strategy to relieve patients suffering from persistent itch without compromising immune defense in the skin.
The second part of the project revealed the existence of two subtypes of sensory neurons with distinct roles in skin inflammation:
Trpv1+ neurons (peptidergic): These help regulate inflammation. Their removal worsened the inflammatory response, notably by increasing neutrophil infiltration, but had no impact on scratching behavior.
MrgprD+ neurons (non-peptidergic): These appear to be directly involved in itch. During skin inflammation, they adopt a transient regeneration program. Their elimination completely abolished scratching behavior without altering inflammation.
Together, these findings demonstrate that inflammation and itch are controlled by distinct neuronal circuits, capable of adapting to the inflammatory state of the skin. This functional decoupling opens the way for more targeted therapies that could relieve itch without interfering with the skin’s natural immune defenses.
Chronic itch linked to skin diseases such as eczema or contact dermatitis is far more than a minor inconvenience: it profoundly affects the quality of life of those who suffer from it. Our work opens new avenues to better understand these complex mechanisms and to design more targeted treatments.
The first study reveals the key role of a pair of nerve molecules, called Alkal2-Alk, in the development of inflammatory itch. While drugs that block Alk already exist, their significant side effects limit their use. Our research focuses on developing new strategies that specifically target Alkal2. This could lead to treatments that are both more effective and better tolerated.
The second study shows that not all sensory nerves in the skin respond the same way to inflammation. Certain populations of neurons play distinct – and sometimes complementary – roles in pain and itch. Until now, broad approaches made it difficult to separate these contributions. With more precise tools, it is now possible to envision therapies that selectively target the neurons involved, calming both inflammation and itch without interfering with other essential functions.
Together, these discoveries mark an important step forward: they demonstrate that it is possible to better understand the neural circuits that drive chronic itch and pave the way toward innovative, safer, and more personalized treatments for patients.
Atopic dermatitis (AD) and Psoriasis (Pso) are frequent chronic inflammatory skin conditions that affect around 7% and 3% of adults, respectively. These two diseases are driven by different (almost antagonist) immune responses, i.e a type 2 immune response for AD and a type 1/17 immune response for Pso. Recent pre-clinical studies have suggested that nociceptive sensory neurons (nociceptors – which transmit itch and pain messages) could actively participate in the development of the inflammatory response in both diseases, but their precise role is still elusive. In this study, we will combine expertise in neuro-immunology, transcriptomic and chemogenetic to study the role played by nociceptors in chronic mouse models of AD and Pso. This work should shed new lights on the plasticity and function of skin-projecting nociceptors in two important dermatoses and help to identify new “neuro-immune-oriented” therapeutic opportunities.
Project coordination
Lilian BASSO (Institut Toulousain des Maladies Infectieuses et Inflammatoires)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
INFINITy Institut Toulousain des Maladies Infectieuses et Inflammatoires
Help of the ANR 297,696 euros
Beginning and duration of the scientific project:
December 2021
- 36 Months
