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HIF-1α targeted deletion in myeloid cells decreases MDSC accumulation and alters microbiome in neonatal mice
Julian Schwarz1, Jessica Rühle1, Kevin Stephan1
1Tuebingen University Children's Hospital, Department of Neonatology, Tuebingen, Germany.
Abstract:
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 loxP/loxP LysMCre+). We show that in contrast to wildtype mice, where an extensive expansion of MDSC was observed, MDSC expansion in neonatal Hif1a loxP/loxP 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.
Insights
Hypoxia-inducible factor 1α (HIF-1α) regulates myeloid-derived suppressor cells (MDSC) expansion in newborns. Reduced HIF-1α impacts MDSC accumulation, altering the microbiome and T-cell homeostasis during neonatal development.
Area of Science:
- Immunology
- Microbiome Research
- Neonatal Development
Background:
- The newborn immune system must balance pathogen defense with tolerance to commensal microbes.
- Myeloid-derived suppressor cells (MDSC) are crucial for immune tolerance and inflammation control in neonates.
- The role of MDSC in microbiome establishment remains largely unknown.
Purpose of the Study:
- To investigate the impact of hypoxia-inducible factor 1α (HIF-1α) on MDSC accumulation.
- To determine the role of HIF-1α-regulated MDSC in neonatal microbiome establishment.
- To analyze the effects on intestinal T-cell homeostasis.
Main Methods:
- Utilized a mouse model with targeted deletion of HIF-1α in myeloid cells (Hif1a loxP/loxP LysMCre+).
- Compared MDSC expansion, microbiome composition, and T-cell populations between knockout and wildtype neonates.
- Assessed systemic and intestinal immune cell profiles.
Main Results:
- Neonatal Hif1a loxP/loxP LysMCre+ mice exhibited significantly reduced MDSC expansion compared to wildtype.
- Microbiome composition was altered in mice lacking HIF-1α in myeloid cells.
- Intestinal T-cell homeostasis was disrupted in the absence of HIF-1α-mediated MDSC expansion.
Conclusions:
- MDSC play a critical role in regulating inflammation during neonatal microbiome establishment.
- HIF-1α is a key regulator of MDSC homeostasis and function in neonates.
- This study reveals a novel function for MDSC in the context of the developing microbiome.
