Neuro-immune-metabolic interactions mediated by axon guidance cues

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22900
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Osaka University
• Principal Investigator: Nakanishi Yoshimitsu 大阪大学, 医学系研究科, 特任助教 (70882645)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: セマフォリン / 造血 / 脂質代謝 / 交感神経

Outline of Final Research Achievements

Functional coupling of the neural, metabolic, and immune systems is essential for organ development and maintenance, but the molecular mechanisms controlling this network remain unclear. Here, we demonstrate that an axonal guidance cue Semaphorin 6D (Sema6D) combines systemic metabolism and myelopoiesis by tuning sympathetic innervations. Sema6d-/- mice fed a high-fat diet (HFD) exhibited attenuated obesity and enhanced myelopoiesis. Combinational analysis of bone marrow (BM) chimeric and conditional knockout mice revealed that non-hematopoietic and neuron-derived Sema6D is responsible for these phenotypes through Plexin-A4. Notably, Sema6d deficiency led to increased sympathetic innervations in the BM. Consistently, loss of β3-adrenergic receptor signaling resolved metabolic and hematopoietic defects in HFD-fed Sema6d-/- mice. Collectively, these data demonstrate that Sema6D orchestrates systemic metabolism and hematopoiesis by tuning sympathetic innervations.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

交感神経は全身の臓器に分布し、代謝、免疫応答などを制御する。しかし、その分布制御機構や分布異常に伴う代謝・免疫応答の変容に関しては明らかになっていないのが現状である。今回の研究成果は交感神経分布を制御する分子を同定するだけでなく、Sema6Dによる交感神経分布制御の代謝学・免疫学的意義を明らかにするものである。