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DB23-0862 Supplementary_materials-0427.pdf (4.76 MB)

A neural-mast cell axis regulates skin microcirculation in diabetes

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posted on 2024-06-04, 15:34 authored by Xinran Li, Dan Yuan, Peng Zhang, Chenglei Luo, Xinyang Xie, Yue Zhang, Zhengqi Wei, Mingyang Wang, Yunqiu Cai, Yi Zeng, Luying Lai, Delu Che, Hao Ling, Shengjun Shi, Hong-Fei Zhang, Fang Wang, Fengxian Li

Abstract

Changes in microcirculation lead to the progression of organ pathology in diabetes. Although neuroimmune interactions contribute to a variety of conditions, it is still unclear whether abnormal neural activities affect microcirculation related to diabetes. Using laser speckle contrast imaging, we examined the skin of patients with type 2 diabetes and found that their microvascular perfusion was significantly compromised. This phenomenon was recapitulated in a high-fat-diet-driven murine model of type 2 diabetes-like disease. In this setting, although both macrophages and mast cells were enriched in the skin, only mast cells and associated degranulation were critically required for the microvascular impairment. Sensory neurons exhibited enhanced TRPV1 activities, which triggered mast cells to degranulate and compromise skin microcirculation. Chemical and genetic ablation of TRPV1+ nociceptors robustly improve skin microcirculation status. Substance P (SP) is a neuropeptide and was elevated in the skin and sensory neurons in the context of type 2 diabetes. Exogenous administration of SP resulted in impaired skin microcirculation, whereas neuronal knockdown of SP dramatically prevented mast cell degranulation and consequently improved skin microcirculation. Overall, our findings indicate a neural-mast cell axis underlying skin microcirculation disturbance in diabetes and shed light on neuroimmune therapeutics for diabetes-related complications.


Article Highlights

· Impaired microcirculation is a shared feature of various complications in type 2 diabetes. Mechanisms underlying its pathology remain not fully understood. Compared to internal organs, the skin is superficial and accessible for microcirculation observation.

· Whether neuroimmune elements play a role in the skin microcirculation impairment associated with type 2 diabetes.

· Sensory neurons are hypersensitized in diabetes and induce overexpression of substance P that triggers mast cell degranulation and consequently impairs skin microcirculation.

· Neuroimmune modulation sheds light on new strategies for treating microcirculation disturbance in type 2 diabetes.

Funding

Fundamental Research Funds for the Central Universities at Sun Yat-sen University x 22ykqb03

Guangdong Natural Science Funds for Distinguished Young Scholar x 2022B1515020067

Ministry of Science and Technology of the People's Republic of China > National Natural Science Foundation of China 81974192; 82271392; 82073427; 82273511

President Foundation of ZhuJiang Hospital, Southern Medical University x yzjj2022rc02

Technological Innovation 2030-Major Projects of "Brain Science and Brain-like Research" x 2022ZD0206200

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