Sci. Immunol. 4, eaaw3658 & eaax0416 (2019)

IL-33 is a unique nuclear cytokine that serves ‘alarmin’ roles after it is released from cells; however, IL-33 also has homeostatic roles in various tissues, including adipose tissues. In Science Immunology, Spallanzani et al. and Mahlakõiv et al. identify the adipose tissue–resident cells that produce IL-33 at steady state to maintain tissue homeostasis. Lin–Sca-1+ mesenchymal cells that express podoplanin and the growth-factor receptor PDGFRα are the main source of IL-33 in adipose tissues. Spallanzani et al. show that a regulatory feedback axis exists between IL-33+ stromal cells and adipose-resident regulatory T cells that express the IL-33 receptor ST2. Mahlakõiv et al. show that PDGFRα+ IL-33+ mesenchymal cells likewise interact with ST2+ group 2 innate lymphoid cells to promote their expression of IL-5 and recruitment of eosinophils to adipose tissues. Obesity alters this homeostatic cellular network and promotes inflammatory responses.