Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany.
Heidelberg University Children's Hospital, Department of Neonatology, Heidelberg, Germany.
Eur J Immunol. 2023 Jul;53(7):e2250144. doi: 10.1002/eji.202250144. Epub 2023 Apr 26.
The newborn's immune system is faced with the challenge of having to learn quickly to fight off infectious agents, but tolerating the colonization of the body surfaces with commensals without reacting with an excessive inflammatory response. Myeloid-derived suppressor cells (MDSC) are innate immune cells with suppressive activity on other immune cells that regulate fetal-maternal tolerance during pregnancy and control intestinal inflammation in neonates. Until now, nothing is known about the role of MDSC in microbiome establishment. One of the transcription factors regulating MDSC homeostasis is the hypoxia-inducible factor 1α (HIF-1α). We investigated the impact of HIF-1α on MDSC accumulation and microbiome establishment during the neonatal period in a mouse model with targeted deletion of HIF-1α in myeloid cells (Hif1a LysMCre+). We show that in contrast to wildtype mice, where an extensive expansion of MDSC was observed, MDSC expansion in neonatal Hif1a LysMCre+ mice was dramatically reduced both systemically and locally in the intestine. This was accompanied by an altered microbiome composition and intestinal T-cell homeostasis. Our results point toward a role of MDSC in inflammation regulation in the context of microbiome establishment and thus reveal a new aspect of the biological role of MDSC during the neonatal period.
新生儿的免疫系统面临着迅速学习抵御感染因子的挑战，但同时又要容忍体表共生菌的定植，而不产生过度的炎症反应。髓源性抑制细胞（MDSC）是具有抑制活性的先天免疫细胞，可调节妊娠期间的胎儿-母体耐受，并控制新生儿的肠道炎症。直到现在，人们对 MDSC 在微生物组建立中的作用一无所知。调节 MDSC 稳态的转录因子之一是缺氧诱导因子 1α（HIF-1α）。我们在髓系细胞中靶向敲除 HIF-1α 的小鼠模型（Hif1a LysMCre+）中研究了 HIF-1α 对新生儿期 MDSC 积累和微生物组建立的影响。与野生型小鼠相比，我们发现野生型小鼠中观察到 MDSC 的广泛扩增，而在新生 Hif1a LysMCre+ 小鼠中，MDSC 的扩增无论是在全身还是在肠道局部都显著减少。这伴随着微生物组组成和肠道 T 细胞稳态的改变。我们的结果表明 MDSC 在微生物组建立过程中的炎症调节中起作用，从而揭示了 MDSC 在新生儿期的生物学作用的一个新方面。
