公开(公告)号：US20220031807A1

公开(公告)日：2022-02-03

申请号：US17280550

申请日：2019-09-26

申请人： INSERM (Institut National de la Santé et de la Recherche Médicale ,  Université d'Aix Marseille ,  CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS)

发明人： Sophie UGOLINI ,  Guihaume DEBROAS ,  Guillaume HOEFFEL ,  Abdelaziz MOQRICH

IPC分类号： A61K38/19 ,  A61K45/06 ,  A61P17/02 ,  A61P29/00

摘要： The skin is one of first lines of defense against external threats. Tissue-resident macrophages have pivotal functions in tissue-barrier integrity and homeostasis. Upon skin inflammation, a functional crosstalk between the sensory nervous system and tissue-resident immune cells can regulate cutaneous immune responses. However, depending on the pathological context, sensory neurons display pro- or anti-inflammatory regulatory properties. Here the inventors identify, in a model of ultraviolet (UV)-induced skin N damage, a regulatory role for type C low-threshold mechanoreceptor (C-LTMR) sensory neurons on the dynamic of dermal macrophage replacement by inflammatory monocytes through the neuropeptide TAFA4. Tafa4-KO mice present an unresolved fibrotic dermis after UV irradiation. Increased fibrotic score correlates with the upstream persistency of inflammatory monocytes and their MHC-II+ macrophage progeny. Bone marrow chimera revealed that inflammatory monocyte differentiation towards CD206+ dermal macrophage is increased in Tafa4KO recipient. Finally, intradermal injection of TAFA4 at the site of UV irradiation reduces inflammatory monocytes accumulation and skin inflammation in Tafa4-KO mice. The results provide new insight about tissue-resident macrophages dynamic during the resolution of skin fibrosis and thus renders credible the use of TAFA4 for the treatment of skin inflammation.