Healing power of neuroimmune interactions in the skin
Sophie Ugolini's team (Inserm/CNRS/Aix-Marseille University), in collaboration with Aziz Moqrich's laboratory at the Developmental Biology Institute of Marseille (IBDM), has shown that the neuropeptide TAFA4, produced in the skin by a subset of sensory neurons, has remarkable anti-inflammatory and healing properties. This discovery could have interesting therapeutic applications in inflammatory diseases, for example in severe forms of COVID-19.
Overexposure of the skin to UV light causes sunburn, which is characterized by destruction of the epidermis and inflammation of the underlying dermis. Such tissue damage induces a complex inflammatory response that must be tightly regulated to prevent persistent injury and impaired healing. Tissue-resident macrophages have a key role in tissue repair, but the precise molecular mechanisms that regulate the balance between inflammatory and pro-repair macrophage responses during healing remain poorly understood. Sunburn is also characterized by a transient phase of painful hypersensitivity, which is mediated by the activation of specialized skin-innervating sensory neurons. The group demonstrated a major role for sensory neurons in promoting the tissue-repair function of macrophages in a sunburn-like model of skin damage in mice. The conditional ablation of sensory neurons expressing the Gαi-interacting protein (GINIP) resulted in defective tissue regeneration and in dermal fibrosis. Elucidation of the underlying molecular mechanisms revealed a crucial role for the neuropeptide TAFA4, which is produced in the skin by C-low threshold mechanoreceptors—a subset of GINIP+ neurons.
Guillaume Hoeffel, researcher Inserm, and Guilhaume Debroas, PhD student in the team, showed that TAFA4 modulates the inflammatory profile of macrophages directly in vitro. In vivo studies in Tafa4-deficient mice revealed that TAFA4 promotes the production of IL-10 by dermal macrophages after UV-induced skin damage. This TAFA4–IL-10 axis also ensures the survival and maintenance of IL-10+TIM4+ dermal macrophages, reducing skin inflammation and promoting tissue regeneration. These results reveal a neuroimmune regulatory pathway driven by the neuropeptide TAFA4 that promotes the anti-inflammatory functions of macrophages and prevents fibrosis after tissue damage, and could lead to new therapeutic perspectives for inflammatory diseases.
Sensory neuron-derived TAFA4 promotes macrophage tissue repair functions. Guillaume Hoeffel*, Guilhaume Debroas*, Anais Roger, Rafaelle Rossignol, Jordi Gouilly, Caroline Laprie, Lionel Chasson, Pierre Vincent Barbon, Anaïs Balsamo, Ana Reynders, Aziz Moqrich & Sophie Ugolini. Nature (2021). 594(7861):94-99. doi: 10.1038/s41586-021-03563-7 : https://rdcu.be/ckUYr
See also an Highlight article in Nature reviews Immunology: https://rdcu.be/cmysj
Legend: Skin sensory neurons (in red and yellow) are in close contact with resident macrophages (in blue). Confocal microscopy analysis, Pierre-Vincent Barbon.