Prof. Honglin Wang's Team from Shanghai General Hospital Published An Article in Nature Communications Revealing A New Mechanism of Dermal Fibroblast-mediating Hyperinnervation during Skin Inflammation

Link of the original article: https://mp.weixin.qq.com/s/4ZhgqWedvfqYqRv3rqSbMQ

On April 10th, the team led by Professor Honglin Wang, the executive vice president of the Clinical Research Institute and the director of the Precision Research Center for Difficult Diseases of Shanghai General Hospital, published a research article titled "Tenascin C+ papillary fibroblasts facilitate neuro-immune interaction in a mouse model of psoriasis" online in Nature Communications. This study innovatively proposes that an injury/inflammation-induced functional subset of dermal papillary fibroblasts promotes neuro-immune interaction and the pro-inflammatory microenvironment formation in psoriasis, clarifies the mechanism of extracellular matrix protein TNC promotes aberrant neurite outgrowth, providing new perspectives and therapeutic strategies for the local immune microenvironment remodeling during chronic skin inflammation.

Psoriasis is a chronic inflammatory skin disease, often accompanied by multiple complications. It is incurable and easy to relapse, which seriously affects the physical and mental health of patients. Neuroimmune interaction plays an important role in skin inflammation and immune defense. In psoriasis, peripheral sensory nerves, especially nociceptors, aggravate inflammation by promoting pathogenic cytokine secretion such as IL-23 in dermal dendritic cells and IL-17 in T cells via neuropeptides such as calcitonin gene-related peptide (CGRP). However, local cues that lead to hyperinnervation of skin lesions remain unclear.

Denervation caused by trauma or surgery is accompanied by regression of psoriatic lesions, while the lesions often recurred after the restoration of innervation, suggesting that peripheral sensory nerves are a risk factor for the development and maintenance of psoriasis. Prof. Wang's team has previously carried out a pilot study of epidural block therapy for the treatment of psoriasis in cooperation with the Department of Anesthesiology of Ruijin Hospital. Targeting sensory nerves achieved good clinical efficacy and the relevant results were published in the Journal of Investigative Dermatology. To further explore the cause of hyperinnervation in psoriatic lesions, the research team turned to fibroblast, an important cutaneous stromal cell subset.

The research team genetically labeled and visualized dermal fibroblast lineage cells with a PdgfraDreER-tdTomato mouse strain, then systemically analyzed dermal fibroblast subsets of untreated and psoriasiform skin with single-cell RNA sequencing. They found a distinct inflammation-induced Tnc+ fibroblast subpopulation featuring pro-axonogenesis transcriptional hallmarks. Using whole-mount fluorescence imaging, the researchers characterized that mouse psoriasiform lesions exhibited aberrant neurite outgrowth compared with normal skin. A TncDreER-tdTomato fluorescent reporter mice strain was then generated, the researchers showed that the inflammation-induced Tnc+ fibroblast subpopulation was localized at the dermal-epidermal junction, and the papillary dermis beneath the epidermis is a hot spot where fibroblasts, peripheral nerves, and T cells interact closely. Compared with the control group, TNC+ fibroblasts significantly boosted neurite outgrowth of co-cultured neurons, and this effect is mediated by the ERK pathway but not dependent on direct contact with the neuron cell body. Conditional knockout of TNC in fibroblasts suppressed hyperinnervation, inflammatory immune cell infiltration, and alleviated skin inflammation in IMQ-induced psoriasis mouse model. Denervation experiments revealed the pro-inflammatory effect of TNC was dependent on peripheral nociceptors. Dermal γδT cells are the main source of pathogenic type 17 inflammatory cytokines, and single-cell sequencing revealed that they were regulated by postsynaptic signals. With Nav1.8tdTomatoIL-17AEGFP dual reporter mice, the researhers demonstrate the dynamic distribution of IL-17A+ T cells and their close interaction with peripheral sensory nerves at different disease stages, providing new evidence for neuroimmune interactions during skin inflammation.

This work was supported by the National Natural Science Foundation of China Original Exploration Program (82050009), the National Key Research and Development Program of the Ministry of Science and Technology (2020YFA0112900), the National Science Fund of China (81930088, 82070509, 82073428, 82101909, 82103719, 82203914), Clinical Research Plan of Shanghai Shenkang Hospital Development Center (SHDC2020CR3061B), the Nature Science Foundation of Shanghai Science and Technology Committee (20ZR1447400), Scientific and Technological Innovation Action Plan (22140903100, 22QA1407600), SJTU Trans-med Awards Research (20210102), and Integrated innovation fund of Shanghai Jiao Tong University (2021JCPT04). The first authors of this article are Cai Xiaojie, a doctorate candidate in Wang Honglin's team, and Han Maoying, a doctorate candidate from Zhou Bin's team at the Center for Excellence in Molecular and Cell Science, Chinese Academy of Sciences. Professor Wang Honglin and Principal Investigator Zhou Bin jointly supervised this research.