🩺 Itching and Skin Inflammation: The surprising involvement of our neurons

Contact dermatitis (CD) is a common acute skin condition affecting about 20% of the population, characterized by hypersensitivity to chemical allergens, inflammation, and severe itching. The latter results from the activation in the skin of sensory endings of several distinct populations of sensory neurons collectively known as nociceptors. Their role is to transmit pain and itching to the brain via the spinal cord, triggering behavioral responses such as scratching.


Recently, it has also been shown that nociceptors can regulate the response of many types of immune cells involved in contact dermatitis, notably neutrophils (white blood cells that destroy pathogens). However, the individual role of different nociceptor populations in the development of CD has remained unknown until now.

In a study led by Nicolas Gaudenzio and Lilian Basso, Inserm researchers at the Toulouse Institute of Infectious and Inflammatory Diseases (Inserm/CNRS/University of Toulouse), scientists identified that different neuronal circuits independently control the inflammatory response and itching in CD.

The research team combined genetic and pharmacological approaches in a mouse model of CD. By isolating the neurons that specifically innervate the skin during cutaneous inflammation, they compared their RNA sequences cell by cell and identified two populations of nociceptors activated differently: one population of so-called "non-peptidergic" nociceptors, which underwent changes across their entire RNA, and another population of so-called "peptidergic" nociceptors, which only showed a few discrete changes.

The researchers then observed that reducing peptidergic nociceptors at a skin lesion site was associated with a strong increase in inflammation with heightened local production of neutrophils, without any relief from the itching sensation. Conversely, reducing the non-peptidergic nociceptor population was associated with a drastic decrease in itching without worsening inflammation.

Surprisingly, the anti-inflammatory role of peptidergic nociceptors seems to oppose their typically pro-inflammatory effects in other contexts of skin conditions, such as atopic dermatitis or psoriasis. "Peptidergic nociceptors appear to be involved in regulating the immune response by limiting local neutrophil production," says Lilian Basso. "This ability seems to be strongly linked to the inflammatory context in which they are activated, and also to the role of neutrophils in that context: if it is beneficial, the nociceptors will have a pro-inflammatory action, and if it is harmful, their action will be more anti-inflammatory."

The research team also observed a healing function of the non-peptidergic nociceptor population in damaged skin tissues. "It is known that wound healing, which also occurs in inflammatory skin conditions, is accompanied by itching. Our study suggests that this itching sensation could actually be a sign of the contribution of non-peptidergic nociceptors to tissue healing," explains Tiphaine Voisin, Inserm researcher and first author of the study.

These results therefore reveal the presence of two distinct and adaptive neuronal circuits that would independently regulate inflammation via peptidergic nociceptors, and skin itching via non-peptidergic nociceptors.

"Overall, our results highlight the importance of considering nociceptor plasticity in dermatological disorders in order to allow a more precise analysis of the neuronal circuits involved in regulating different manifestations of certain pathologies. This new nuanced understanding of how nociceptors contribute to inflammation and itching could pave the way for innovative therapeutic strategies to simultaneously manage inflammation and itching in CD and other skin disorders," concludes Nicolas Gaudenzio.