Cell Stem Cell:腎上腺素能神經通過IL-22信號傳導調節腸道再生

2023年8月18日,來自美國基因泰克公司Frederic J. de Sauvage研究組在學術期刊《細胞-干細胞》發表了標題為”Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells.“的研究成果。發現腎上腺素能神經通過3型先天淋巴細胞(ILC3s)分泌的IL-22信號傳導調節腸道再生。

 

腸道非常容易受到影響,并在癌癥治療過程中受到改變DNA的試劑(如放療和化療)造成的惡劣條件的影響。例如,許多胃腸道腫瘤患者接受放療,這種治療往往也會損害健康腸道,影響它的再生能力。因此,了解腸道上皮的再生是如何發生的非常重要。

據介紹,腸上皮細胞具有較高的內在周轉率,上皮的準確更新取決于微環境。腸道由密集的周圍神經網絡支配,該網絡控制腸道生理學的各個方面。然而,神經元在調節上皮細胞再生中的作用仍然未知。

 

研究人員探究了腸道支配腎上腺素能神經對照射(IR)誘導損傷后上皮細胞修復的影響。研究人員觀察到,IR后小腸中的腎上腺素能神經密度增加,而化學腎上腺素能去神經支配損害了上皮再生。單細胞RNA測序結果顯示,去神經支配動物在IR后IL-22信號傳導減少。藥理和遺傳學工具相結合,研究人員證明β-腎上腺素能受體信號傳導促進IR后ILC3s產生IL-22,進而促進上皮再生。

 

這些結果揭示了對腸道再生非常重要的腎上腺素能-ILC3通路,為如何抵消胃腸癌患者放療的副作用的添加新思路。

 

Highlights

? Adrenergic denervation impairs intestinal regeneration post IR-induced injury

? scRNA-seq reveals a reduction in epithelial IL-22 signaling upon denervation

? IL-22 levels from ILC3s post injury are regulated downstream of β-adrenergic receptors

? IL-22 mediates the effects of adrenergic nerves on intestinal regeneration

Summary

The intestinal epithelium has high intrinsic turnover rate, and the precise renewal of the epithelium is dependent on the microenvironment. The intestine is innervated by a dense network of peripheral nerves that controls various aspects of intestinal physiology. However, the role of neurons in regulating epithelial cell regeneration remains largely unknown. Here, we investigated the effects of gut-innervating adrenergic nerves on epithelial cell repair following irradiation (IR)-induced injury. We observed that adrenergic nerve density in the small intestine increased post IR, while chemical adrenergic denervation impaired epithelial regeneration. Single-cell RNA sequencing experiments revealed a decrease in IL-22 signaling post IR in denervated animals. Combining pharmacologic and genetic tools, we demonstrate that β-adrenergic receptor signaling drives IL-22 production from type 3 innate lymphoid cells (ILC3s) post IR, which in turn promotes epithelial regeneration. These results define an adrenergic-ILC3 axis important for intestinal regeneration.

 

文章來源:

Putianqi Wang, Noelyn Kljavin et al, Adrenergic nerves regulate intestinal regeneration through IL-22 signaling from type 3 innate lymphoid cells. DOI: 10.1016/j.stem.2023.07.013,Cell Stem Cell: 最新IF:25.269

 

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