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

ABSTRACT: 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.

SUBMITTER: Mahlakoiv T

PROVIDER: S-EPMC6766755 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Mahlakõiv T T Flamar A-L AL Johnston L K LK Moriyama S S Putzel G G GG Bryce P J PJ Artis D D

Science immunology 20190501 35

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 ...[more]

PMID: 31053655

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Project description:IntroductionInterleukin-33 (IL-33), the ligand for the receptor ST2, is abundant in adipose tissue, including preadipocytes, adipocytes, and endothelial cells. The IL-33/ST2 axis is protective against obesity, insulin resistance, and type 2 diabetes (T2D) in animal models. We determined whether adipose tissue IL-33 was associated with glycated hemoglobin (HbA1c), as well as mediators of inflammation and immune regulation and beiging of adipose tissue, among individuals with varying degrees of glycemia.Materials and methodsA total of 91 adults with normoglycemia, prediabetes, and T2D were included. After measuring their anthropometric and biochemical parameters, subcutaneous adipose tissue samples were isolated and mRNA expression of cytokines, chemokines, chemokine receptors, pattern recognition receptors, and mediators involved in beiging of adipose tissue were measured.ResultsAdipose tissue IL-33 was inversely associated with HbA1c in individuals with normoglycemia and T2D but not in those with prediabetes and was inversely correlated with fasting plasma glucose in individuals with T2D and with a better glycemic control. IL-33-to-ST2 ratio was inversely correlated with HbA1c in individuals with normoglycemia but not in those with prediabetes or T2D. IL-33 was directly associated with ST2, CD302, fibrinogen-like protein 2 (FGL2), and PR domain containing 16 (PRDM16) but inversely correlated with chemokine (C-C motif) ligand (CCL) 7 and CCL8 in individuals with normoglycemia. Similarly, IL-33 was directly associated with ST2, CD302, FGL2, PRDM16, and, additionally, toll-like receptor (TLR) 3 and IL-12A in individuals with T2D. However, IL-33 was not associated with any of these mediators but was directly and strongly associated with TLR9 in individuals with prediabetes.ConclusionsIL-33 and/or IL-33/ST2 dynamics and biological functions may play a role in overall glycemia among humans and may represent a novel target by which glucose-lowering managements confer their beneficial effects.

Project description:OBJECTIVE:Despite the large body of work describing the tumor suppressor functions of Phosphatase and tensin homologue deleted on chromosome ten (PTEN), its roles in adipose homeostasis of adult animals are not yet fully understood. Here, we sought to determine the role of PTEN in whole-body adipose homeostasis. METHODS:We genetically manipulated PTEN in specific fat depots through recombinant adeno-associated viral vector (rAAV)-based gene transfer of Cre recombinase to adult PTENflox mice. Additionally, we used a denervation agent, 6OHDA, to assess the role of sympathetic signaling in PTEN-related adipose remodeling. Furthermore, we chemically manipulated AKT signaling via a pan-AKT inhibitor, MK-2206, to assess the role of AKT in PTEN-related adipose remodeling. Finally, to understand the role of leptin and central signaling on peripheral tissues, we knocked down hypothalamic leptin receptor with a microRNA delivered by a rAAV vector. RESULTS:Knockdown PTEN in individual fat depot resulted in massive expansion of the affected fat depot through activation of AKT signaling associated with suppression of lipolysis and induction of leptin. This hypertrophic expansion of the affected fat depot led to upregulation of PTEN level, higher lipolysis, and induction of white fat browning in other fat depots, and the compensatory reduced fat mass to maintain a set point of whole-body adiposity. Administration of AKT inhibitor MK-2206 prevented the adipose PTEN knockdown-associated effects. 6OHDA-mediated denervation demonstrated that sympathetic innervation was required for the PTEN knockdown-induced adipose redistribution. Knockdown hypothalamic leptin receptor attenuated the adipose redistribution induced by PTEN deficiency in individual fat depot. CONCLUSIONS:Our results demonstrate the essential role of PTEN in adipose homeostasis, including mass and distribution in adulthood, and reveal an "adipose PTEN-leptin-sympathetic nervous system" feedback loop to maintain a set point of adipose PTEN and whole-body adiposity.

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

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

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