Muscularis macrophage development in the absence of an enteric nervous system
Muscularis macrophage development in the absence of an enteric nervous system
复制标题
DOI：
10.1073/pnas.1802490115
复制
发表时间：
2018-05-01
影响因子：
11.1
通讯作者：
Heuckeroth, Robert O.
中科院分区：
文献类型：
--
作者：
Avetisyan, Marina;Rood, Julia E.;Heuckeroth, Robert O.
肠道神经系统调节组织常驻肌层巨噬细胞（MM）的炎症表型，在成年小鼠中，肠道神经元是集落刺激因子1 （CSF1）的主要局部来源，CSF1是MM存活所需的蛋白质。令人惊讶的是，我们发现在发育过程中，MM在肠神经元之前定植肠道。这引起了人们对MM在肠内定植是否需要神经元来源的CSF1的质疑。为了确定MM的发育是否需要肠神经支配，我们分析了小肠或结肠中没有肠神经系统的新生Ret(-/-) （Ret KO）小鼠的MM。我们在Ret KO肠中发现了正常数量的模式良好的MM。同样，从巨结肠患者获得的人神经节结肠中MM的丰度和分布是正常的。我们还发现Cajal的内皮细胞和间质细胞是发育中的肠中CSF1的主要来源。此外，来自新生儿Ret KOs的MM在基线激活状态或响应脂多糖的细胞因子产生方面与对照组没有区别。出乎意料的是，这些数据表明肠神经系统对于MM在肠道中的定植和模式是必不可少的，并且表明MM和肠神经系统之间的调节相互作用是在出生后建立的。
The nervous system of the bowel regulates the inflammatory phenotype of tissue resident muscularis macrophages (MM), and in adult mice, enteric neurons are the main local source of colony stimulating factor 1 (CSF1), a protein required for MM survival. Surprisingly, we find that during development MM colonize the bowel before enteric neurons. This calls into question the requirement for neuron-derived CSF1 for MM colonization of the bowel. To determine if intestinal innervation is required for MM development, we analyzed MM of neonatal Ret(-/-) (Ret KO) mice that have no enteric nervous system in small bowel or colon. We found normal numbers of well-patterned MM in Ret KO bowel. Similarly, the abundance and distribution of MM in aganglionic human colon obtained from Hirschsprung disease patients was normal. We also identify endothelial cells and interstitial cells of Cajal as the main sources of CSF1 in the developing bowel. Additionally, MM from neonatal Ret KOs do not differ from controls in baseline activation status or cytokine-production in response to lipopolysaccharide. Unexpectedly, these data demonstrate that the enteric nervous system is dispensable for MM colonization and patterning in the bowel, and suggest that modulatory interactions between MM and the bowel nervous system are established postnatally.