A Neuron–Mast Cell Axis Regulates Skin Microcirculation in Diabetes.

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 replicated 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 improved 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 neuron–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 identified. Compared with internal organs, the skin is superficial and accessible for microcirculation observation. The role neuroimmune elements play in skin microcirculation impairment associated with type 2 diabetes was investigated. Sensory neurons are hypersensitized in diabetes and induce overexpression of substance P, which triggers mast cell degranulation and consequently impairs skin microcirculation. Neuroimmune modulation sheds light on new strategies for treating microcirculation disturbance in type 2 diabetes. [ABSTRACT FROM AUTHOR]