The role of the IL-9‒NLRP3 axis in insulin resistance and adipose tissue inflammation during diet-induced obesity

  • Cell Mol Immunol. 2025 Sep 18. doi: 10.1038/s41423-025-01340-4.
Marc P Hübner  1  2 ,  Dennis de Coninck  3 ,  Benjamin Lenz  1 ,  Jayagopi Surendar  4 ,  Marianne Koschel  1 ,  Narcisse Victor Tchamatchoua Gandjui  5  6 ,  Beng Amuam Andrew  5  6 ,  Lucy Cho Nchang  5  6 ,  Anita Obi Bate Ebob  5  6 ,  Fanny Fri Fombad  5  6 ,  Lisa Marie Springer  1 ,  Lars Eppe  7 ,  Frank A Schildberg  4 ,  Samuel Wanji  5  6 ,  Achim Hoerauf  1  2 ,  Alexander Pfeifer  3 ,  Indulekha Karunakaran  8
Affiliations
  • 1. Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany.
  • 2. German Center for Infection Research (DZIF), partner site Bonn-Cologne, Bonn, Germany.
  • 3. Institute of Pharmacology and Toxicology, University Hospital Bonn, Bonn, Germany.
  • 4. Department of Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany.
  • 5. Parasite and Vector Biology Research Unit, Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Buea, Cameroon.
  • 6. Research Foundation in Tropical Diseases and the Environment, Buea, Cameroon.
  • 7. University of Oslo, Oslo, Norway.
  • 8. Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Bonn, Germany. [email protected].
PMID: 40962954 DOI: 10.1038/s41423-025-01340-4
Abstract

Despite the proven beneficial role of type 2 cytokines in diabetes and obesity, IL-9, a predominant Th2 cytokine, has not been investigated in this context. The present study characterized the role of IL-9 signaling in obesity and metabolic dysfunction. We found decreased IL-9 levels in human type 2 diabetes patients and decreased IL-9 signaling in high-fat diet (HFD)-induced obese mice. On the Other hand, recombinant IL-9 (rIL-9) treatment reversed Insulin insensitivity and inflammation following HFD consumption. IL-9R knockout (KO) mice fed a HFD presented faster weight gain, impaired glucose and Insulin tolerance, defective Insulin signaling, increased adipocyte size, and decreased energy expenditure. In the adipose tissue of HFD-fed IL-9R KO mice, a significant increase in the number of CD11c+ macrophages and a decrease in the number of RELMα+ macrophages, eosinophils and ILC2s were observed, along with increased TNF, decreased Adiponectin production and increased expression of NLRP3. In vitro treatment of human and mouse macrophages with rIL-9 decreased the release of NLRP3-induced IL-1β and IL-18. In vivo treatment of HFD-fed IL-9R KO mice with a pharmacological inhibitor of the NLRP3 inflammasome rescued body weight, Insulin sensitivity and adipose tissue inflammation. Mechanistically, the STAT5 protein was found to be important for the IL-9-induced inhibition of the NLRP3 inflammasome in adipose tissue. In addition, we also demonstrated a potential role for IL-9 in the protective effects of helminth immunomodulation during obesity and Insulin resistance in filaria-infected humans and in an animal model. Taken together, the results of this study highlight that IL-9 signaling improves Insulin signaling by inhibiting NLRP3-induced inflammation.

Keywords
Helminths; IL-9 signaling; Inflammasome; Inflammation; Obesity; insulin resistance.
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