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Article

The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

1
Institute of Molecular Cell Biology, Jena University Hospital, D-07745 Jena, Germany
2
Department of Neonatology, Heidelberg University Children’s Hospital, D-69120 Heidelberg, Germany
3
Leibniz Institute on Ageing, Fritz Lipmann Institute, D-07745 Jena, Germany
4
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, D-07747 Jena, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Markus Ritter
Int. J. Mol. Sci. 2021, 22(5), 2578; https://doi.org/10.3390/ijms22052578
Received: 29 December 2020 / Revised: 23 January 2021 / Accepted: 26 February 2021 / Published: 4 March 2021
(This article belongs to the Special Issue Molecular, Cellular and Systemic Signature of Microglia)
Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it. View Full-Text
Keywords: microglia; immunometabolism; innate immune memory; LPS; PI3Kγ; glycolysis; pentose phosphate pathway; OXPHOS; OCR; ECAR microglia; immunometabolism; innate immune memory; LPS; PI3Kγ; glycolysis; pentose phosphate pathway; OXPHOS; OCR; ECAR
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MDPI and ACS Style

Lajqi, T.; Marx, C.; Hudalla, H.; Haas, F.; Große, S.; Wang, Z.-Q.; Heller, R.; Bauer, M.; Wetzker, R.; Bauer, R. The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory. Int. J. Mol. Sci. 2021, 22, 2578. https://doi.org/10.3390/ijms22052578

AMA Style

Lajqi T, Marx C, Hudalla H, Haas F, Große S, Wang Z-Q, Heller R, Bauer M, Wetzker R, Bauer R. The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory. International Journal of Molecular Sciences. 2021; 22(5):2578. https://doi.org/10.3390/ijms22052578

Chicago/Turabian Style

Lajqi, Trim, Christian Marx, Hannes Hudalla, Fabienne Haas, Silke Große, Zhao-Qi Wang, Regine Heller, Michael Bauer, Reinhard Wetzker, and Reinhard Bauer. 2021. "The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory" International Journal of Molecular Sciences 22, no. 5: 2578. https://doi.org/10.3390/ijms22052578

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