2. Academic Validation
  3. RORα negatively regulates BCG-induced trained immunity

RORα negatively regulates BCG-induced trained immunity

  • Cell Immunol. 2024 Aug 15:403-404:104862. doi: 10.1016/j.cellimm.2024.104862.
Gizem Kilic 1,  Vasiliki Matzaraki 2,  Ozlem Bulut 2,  Ilayda Baydemir 2,  Anaisa V Ferreira 2,  Katrin Rabold 2,  Simone J C F M Moorlag 2,  Valerie A C M Koeken 3,  L Charlotte J de Bree 2,  Vera P Mourits 2,  Leo A B Joosten 4,  Jorge Domínguez-Andrés 2,  Mihai G Netea 5
Affiliations

Affiliations

  • 1 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address: Gizem.Kilic@radboudumc.nl.
  • 2 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 3 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Research Centre Innovations in Care, Rotterdam University of Applied Sciences, Rotterdam, The Netherlands.
  • 4 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Medical Genetics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
  • 5 Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands; Department for Immunology and Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany.
PMID: 39159505 DOI: 10.1016/j.cellimm.2024.104862
Abstract

Trained immunity is a long-lasting change in the responsiveness of innate immune cells, leading to a stronger response upon an unrelated secondary challenge. Epigenetic, transcriptional, and metabolic reprogramming contribute to the development of trained immunity. By investigating the impact of gene variants on trained immunity responses after Bacillus Calmette-Guérin (BCG) vaccination, we identified a strong association between polymorphisms in the RORA gene and BCG-induced trained immunity in PBMCs isolated from healthy human donors. RORα, encoded by the RORA gene in humans, is a nuclear receptor and a transcription factor, regulating genes involved in circadian rhythm, inflammation, Cholesterol, and lipid metabolism. We found that natural RORα agonists in the circulation negatively correlate with the strength of trained immunity responses after BCG vaccination. Moreover, pharmacological inhibition of RORα in human PBMCs led to higher cytokine production capacity and boosted trained immunity induction by BCG. Blocking RORα activity also resulted in morphological changes and increased ROS and lactate production of BCG-trained cells. Blocking Lactate Dehydrogenase A (LDHA) and glycolysis with sodium oxamate reduced the cytokine production capacity of cells trained with a combination of BCG and the RORα agonist. In conclusion, this study highlights the potential role of RORα in trained immunity, and its impact on human vaccination and diseases should be further investigated.

Keywords

BCG; Immunometabolism; RORA; Trained immunity.

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