Skip to main content

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

Cellular & molecular immunology

Authors: Marc P Hübner, Dennis de Coninck, Benjamin Lenz, Jayagopi Surendar, Marianne Koschel, Narcisse Victor Tchamatchoua Gandjui, Beng Amuam Andrew, Lucy Cho Nchang, Anita Obi Bate Ebob, Fanny Fri Fombad, Lisa Marie Springer, Lars Eppe, Frank A Schildberg, Samuel Wanji, Achim Hoerauf, Alexander Pfeifer, Indulekha Karunakaran

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.

© 2025. The Author(s).

PMID: 40962954

Participating cluster members