Glucose-oxygen deprivation constrains HMGCR function and Rac1 prenylation and activates the NLRP3 inflammasome in human monocytes

Author:

Raulien Nora12ORCID,Friedrich Kathleen1ORCID,Strobel Sarah1ORCID,Raps Stefanie1,Hecker Friederike1ORCID,Pierer Matthias1,Schilling Erik1ORCID,Lainka Elke3ORCID,Kallinich Tilmann4ORCID,Baumann Sven5,Fritz-Wallace Katarina5ORCID,Rolle-Kampczyk Ulrike5ORCID,von Bergen Martin567ORCID,Aigner Achim8ORCID,Ewe Alexander8ORCID,Schett Georg910ORCID,Cross Michael11ORCID,Rossol Manuela112ORCID,Wagner Ulf1ORCID

Affiliation:

1. Division of Rheumatology, Department of Endocrinology, Nephrology, Rheumatology, Leipzig University, Leipzig, Germany.

2. Institute of Anatomy, University Leipzig, Leipzig, Germany.

3. Department of Pediatric Gastroenterology, Hepatology and Liver Transplantation, University Children’s Hospital Essen, Essen, Germany.

4. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.

5. Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research GmbH, Leipzig, Germany.

6. Institute for Biochemistry, Faculty of Life Sciences, Leipzig University, Leipzig, Germany.

7. German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany.

8. Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, Leipzig University, Leipzig, Germany.

9. Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.

10. Deutsches Zentrum Immuntherapie, Friedrich-Alexander University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.

11. Leipzig Medical Center, Clinic for Hematology and Cell Therapy, University Clinic Leipzig, Leipzig, Germany.

12. Molecular Immunology, Faculty of Health Sciences, Brandenburg Technische Universität Cottbus-Senftenberg, Senftenberg, Germany.

Abstract

Hypoxia and low glucose abundance often occur simultaneously at sites of inflammation. In monocytes and macrophages, glucose-oxygen deprivation stimulates the assembly of the NLRP3 inflammasome to generate the proinflammatory cytokine IL-1β. We found that concomitant glucose deprivation and hypoxia activated the NLRP3 inflammasome by constraining the function of HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate kinase pathway. HMGCR is involved in the synthesis of geranylgeranyl pyrophosphate (GGPP), which is required for the prenylation and lipid membrane integration of proteins. Under glucose-oxygen deprivation, GGPP synthesis was decreased, leading to reduced prenylation of the small GTPase Rac1, increased binding of nonprenylated Rac1 to the scaffolding protein IQGAP1, and enhanced activation of the NLRP3 inflammasome. In response to restricted oxygen and glucose supply, patient monocytes with a compromised mevalonate pathway due to mevalonate kinase deficiency or Muckle-Wells syndrome released more IL-1β than did control monocytes. Thus, reduced GGPP synthesis due to inhibition of HMGCR under glucose-oxygen deprivation results in proinflammatory innate responses, which are normally kept in check by the prenylation of Rac1. We suggest that this mechanism is also active in inflammatory autoimmune conditions.

Publisher

American Association for the Advancement of Science (AAAS)

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