Stromal cells maintain immune cell homeostasis in adipose tissue via production of interleukin-33.

Tissue-resident stromal cells control innate lymphoid cell–dependent immune homeostasis in adipose tissue. Stromal sources of IL-33 in fat depots: White adipose tissue (WAT) is home to T_regs and group 2 innate lymphoid cells (ILC2s) that help keep inflammation under check. Two studies in this week's issue probe WAT in search of cells producing the alarmin cytokine interleukin-33 (IL-33) that regulates T_regs and ILC2s. Spallanzani et al. used single-cell RNA sequencing to characterize visceral WAT stromal cells and defined five distinct subtypes, with subtypes 1 to 3 producing IL-33 and subtypes 4 and 5 resembling adipocyte precursors. Mahlakõiv et al. identified adipose stem and progenitor cells as a source of IL-33 in all WAT depots and mesothelial cells as an additional source of IL-33 in visceral WAT. These studies improve our understanding of WAT stromal cell diversity and how the stromal cell landscape responds to physiological or pathological variations. See related Research Article by Spallanzani et al. Obesity is driven by chronic low-grade inflammation resulting from dysregulated immune cell accumulation and function in white adipose tissue (WAT). Interleukin-33 (IL-33) is a key cytokine that controls innate and adaptive immune cell activity and immune homeostasis in WAT, although the sources of IL-33 have remained controversial. Here, we show that WAT-resident mesenchyme-derived stromal cells are the dominant producers of IL-33. Adipose stem and progenitor cells (ASPCs) produced IL-33 in all WAT depots, whereas mesothelial cells served as an additional source of IL-33 in visceral WAT. ASPC-derived IL-33 promoted a regulatory circuit that maintained an immune tone in WAT via the induction of group 2 innate lymphoid cell–derived type 2 cytokines and maintenance of eosinophils, whereas mesothelial IL-33 also acted as an alarmin by inducing peritoneal immune response upon infection. Together, these data reveal a previously unrecognized regulatory network between tissue-resident progenitor cells and innate lymphoid cells that maintains immune homeostasis in adipose tissue. [ABSTRACT FROM AUTHOR]