JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation
Abstract Disease tolerance is a key defense mechanism that limits damage to the host without directly reducing pathogen levels. In malaria, these mechanisms are essential for preventing severe disease and death but remain poorly understood. In this study, we show that glucocorticoid receptor (GR)-me...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2025-07-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-025-00264-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849332219833745408 |
|---|---|
| author | Fran Prenen Leen Vandermosten Sofie Knoops Emilie Pollenus Hendrik Possemiers Pauline Dagneau de Richecour Giorgio Caratti Christopher Cawthorne Sabine Vettorazzi Yevva Cranshoff Dominique Schols Sandra Claes Christophe M Deroose Uwe Himmelreich Jan Tuckermann Philippe E Van den Steen |
| author_facet | Fran Prenen Leen Vandermosten Sofie Knoops Emilie Pollenus Hendrik Possemiers Pauline Dagneau de Richecour Giorgio Caratti Christopher Cawthorne Sabine Vettorazzi Yevva Cranshoff Dominique Schols Sandra Claes Christophe M Deroose Uwe Himmelreich Jan Tuckermann Philippe E Van den Steen |
| author_sort | Fran Prenen |
| collection | DOAJ |
| description | Abstract Disease tolerance is a key defense mechanism that limits damage to the host without directly reducing pathogen levels. In malaria, these mechanisms are essential for preventing severe disease and death but remain poorly understood. In this study, we show that glucocorticoid receptor (GR)-mediated processes play a vital role in disease tolerance during Plasmodium chabaudi AS infection. GR deletion in infected mice resulted in lethal hypoglycemia and a cytokine storm. Hypoglycemia was driven by severe metabolic dysfunction in the liver and spleen, characterized by increased glucose uptake, glycogen depletion, a dominant glycolytic profile and reduced gluconeogenic gene expression. Importantly, this hypoglycemic state was strongly associated with overactivation of the JAK/STAT pathway and excessive cytokine expression. Treatment with the JAK1/2 inhibitor ruxolitinib significantly improved survival by preventing lethal hypoglycemia and suppressing hyperinflammation. Our findings reveal a novel link between GR signaling, STAT3 activation, cytokine expression and glucose metabolism during severe malaria. This underscores the critical role of GR-mediated processes in disease tolerance and highlights ruxolitinib as a promising adjuvant therapy for managing life-threatening metabolic complications in malaria. |
| format | Article |
| id | doaj-art-805c53801a7a461ca775156d1371edc3 |
| institution | Kabale University |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-805c53801a7a461ca775156d1371edc32025-08-20T03:46:16ZengSpringer NatureEMBO Molecular Medicine1757-46842025-07-011782040207010.1038/s44321-025-00264-wJAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammationFran Prenen0Leen Vandermosten1Sofie Knoops2Emilie Pollenus3Hendrik Possemiers4Pauline Dagneau de Richecour5Giorgio Caratti6Christopher Cawthorne7Sabine Vettorazzi8Yevva Cranshoff9Dominique Schols10Sandra Claes11Christophe M Deroose12Uwe Himmelreich13Jan Tuckermann14Philippe E Van den Steen15Laboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenLaboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenLaboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenLaboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenLaboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenLaboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenInstitute of Molecular Endocrinology and Physiology, German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm UniversityNuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU LeuvenInstitute of Molecular Endocrinology and Physiology, German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm UniversityLaboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenLaboratory of Molecular, Structural and Translational Virology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenLaboratory of Molecular, Structural and Translational Virology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenNuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU LeuvenBiomedical MRI, Department of Imaging and Pathology, 3000 KU LeuvenInstitute of Molecular Endocrinology and Physiology, German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm UniversityLaboratory of Immunoparasitology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU LeuvenAbstract Disease tolerance is a key defense mechanism that limits damage to the host without directly reducing pathogen levels. In malaria, these mechanisms are essential for preventing severe disease and death but remain poorly understood. In this study, we show that glucocorticoid receptor (GR)-mediated processes play a vital role in disease tolerance during Plasmodium chabaudi AS infection. GR deletion in infected mice resulted in lethal hypoglycemia and a cytokine storm. Hypoglycemia was driven by severe metabolic dysfunction in the liver and spleen, characterized by increased glucose uptake, glycogen depletion, a dominant glycolytic profile and reduced gluconeogenic gene expression. Importantly, this hypoglycemic state was strongly associated with overactivation of the JAK/STAT pathway and excessive cytokine expression. Treatment with the JAK1/2 inhibitor ruxolitinib significantly improved survival by preventing lethal hypoglycemia and suppressing hyperinflammation. Our findings reveal a novel link between GR signaling, STAT3 activation, cytokine expression and glucose metabolism during severe malaria. This underscores the critical role of GR-mediated processes in disease tolerance and highlights ruxolitinib as a promising adjuvant therapy for managing life-threatening metabolic complications in malaria.https://doi.org/10.1038/s44321-025-00264-wGlucocorticoid ReceptorHypoglycemiaMalariaRuxolitinibTolerance |
| spellingShingle | Fran Prenen Leen Vandermosten Sofie Knoops Emilie Pollenus Hendrik Possemiers Pauline Dagneau de Richecour Giorgio Caratti Christopher Cawthorne Sabine Vettorazzi Yevva Cranshoff Dominique Schols Sandra Claes Christophe M Deroose Uwe Himmelreich Jan Tuckermann Philippe E Van den Steen JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation EMBO Molecular Medicine Glucocorticoid Receptor Hypoglycemia Malaria Ruxolitinib Tolerance |
| title | JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation |
| title_full | JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation |
| title_fullStr | JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation |
| title_full_unstemmed | JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation |
| title_short | JAK/STAT inhibition protects glucocorticoid receptor knockout mice from lethal malaria-induced hypoglycemia and hyperinflammation |
| title_sort | jak stat inhibition protects glucocorticoid receptor knockout mice from lethal malaria induced hypoglycemia and hyperinflammation |
| topic | Glucocorticoid Receptor Hypoglycemia Malaria Ruxolitinib Tolerance |
| url | https://doi.org/10.1038/s44321-025-00264-w |
| work_keys_str_mv | AT franprenen jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT leenvandermosten jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT sofieknoops jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT emiliepollenus jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT hendrikpossemiers jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT paulinedagneauderichecour jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT giorgiocaratti jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT christophercawthorne jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT sabinevettorazzi jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT yevvacranshoff jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT dominiqueschols jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT sandraclaes jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT christophemderoose jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT uwehimmelreich jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT jantuckermann jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation AT philippeevandensteen jakstatinhibitionprotectsglucocorticoidreceptorknockoutmicefromlethalmalariainducedhypoglycemiaandhyperinflammation |