Project description:Development of type 2 diabetes mellitus (T2DM) is associated low-grade chronic type 2 inflammation and disturbance of glucose homeostasis. Group 2 innate lymphoid cells (ILC2s) play a critical role in maintaining adipose homeostasis via production of type 2 cytokines. Here, we demonstrate that CB2, a G-protein coupled receptor (GPCR) and member of endocannabinoid system, is expressed on both visceral adipose tissue (VAT)-derived murine and human ILC2s. Moreover, we utilize a combination of ex vivo and in vivo approaches to explore the functional and therapeutic impacts of CB2 engagement on VAT ILC2s in T2DM model. Our results show CB2 stimulation of ILC2s protects against insulin-resistance onset, ameliorates glucose tolerance, and reverses established insulin-resistance. Our mechanistic studies reveal that the therapeutic effects of CB2 are mediated through activation of AKT, ERK1/2 and CREB pathways on ILC2s. The results reveal that CB2 agonist can serve as candidate for prevention and treatment of T2DM.
Project description:Transcriptomal comparison between group 2 innate lymphoid cells (ILC2s) in the murine small intestine (SI-ILC2s) and those in white adipose tissue (WAT-ILC2s).
Project description:Transcriptomal comparison between group 2 innate lymphoid cells (ILC2s) in the murine small intestine (SI-ILC2s) and those in white adipose tissue (WAT-ILC2s)
Project description:ILC2s are highly heterogeneous tissue-resident lymphocytes that regulate inflammation and tissue homeostasis in health and disease. But how they integrate to the respective tissue microenvironment to perform tissue-supportive functions remain poorly defined. Here, we identify neuropilin-1, which is induced postnatally and sustained by lung-derived TGFβ1, as a tissue signature of lung ILC2s. Genetic ablation or pharmacological inhibition of Nrp1 suppresses ILC2s function and protects mice from the development of pulmonary fibrosis. Mechanistically, TGFβ1-Nrp1 signaling enhances ILC2s function and type 2 immunity through upregulation of IL-33 receptor ST2 expression. Our findings identify Nrp1 as a tissue-specific regulator of lung-resident ILC2s activation and highlight Nrp1 as a potential therapeutic target for pulmonary fibrosis
Project description:The perinatal period is a critical window for the distribution of innate tissue-resident immune cells to developing organs. Despite epidemiologic evidence implicating early life environment in risk for allergy, temporally controlled lineage-tracing of ILC2s during this period has not been done. Using complementary fate-mapping approaches and fluorescent reporters of ILC2 activation, we demonstrate that ILC2s appear in multiple organs during late gestation similar to tissue macrophages, but unlike the latter, a majority of peripheral ILC2 pools are generated de novo during a postnatal window. This period was accompanied by systemic ILC2 priming and acquisition of tissue-specific expression profiles. Although perinatal ILC2s are variably replaced with age, the dramatic increases in tissue ILC2s following helminth infection are mediated through local expansion independent of de novo generation by BM hematopoiesis. We provide the first comprehensive temporally controlled fate-mapping of an innate lymphocyte subset with notable nuances as compared to tissue macrophage ontogeny
Project description:Metabolic syndrome is characterized by disturbances in glucose homeostasis and the development of low-grade systemic inflammation, which increase the risk to develop type-2 diabetes mellitus (T2DM). Type-2 innate lymphoid cells (ILC2s) are a recently discovered immune population secreting Th2-cytokines. While previous studies show how ILC2s can play a critical role in the regulation of metabolic homeostasis in the adipose tissue, a therapeutic target capable of modulating ILC2 activation has yet to be identified. Here, we show that GITR, a member of the TNF superfamily, is expressed on both murine and human ILC2s. Strikingly, we demonstrate that GITR engagement of activated, but not naïve, ILC2s improves glucose homeostasis, resulting in both protection against insulin-resistance onset and amelioration of established insulin-resistance. Together, these results highlight the critical role of GITR as a novel therapeutic molecule against T2DM and its fundamental role as an immune checkpoint for activated ILC2s.
