DR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus

Abstract

Disturbances in glucose homeostasis and low-grade chronic inflammation culminate into metabolic syndrome that increase the risk for the development of type 2 diabetes mellitus (T2DM). The recently discovered group 2 innate lymphoid cells (ILC2s) are capable of secreting copious amounts of type 2 cytokines to modulate metabolic homeostasis in adipose tissue. In this study, we have established that expression of Death Receptor 3 (DR3), a member of the TNF superfamily, on visceral adipose tissue (VAT)-derived murine and peripheral blood human ILC2s is inducible by IL-33. We demonstrate that DR3 engages the canonical and/or non-canonical NF-κB pathways, and thus stimulates naïve and co-stimulates IL-33-activated ILC2s. Importantly, DR3 engagement on ILC2s significantly ameliorates glucose tolerance, protects against insulin-resistance onset and remarkably reverses already established insulin-resistance. Taken together, these results convey the potent role of DR3 as an ILC2 regulator and introduce DR3 agonistic treatment as a novel therapeutic avenue for treating T2DM.

CD200–CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma

“…Human blood samples were obtained from male and female healthy donors (age 18–65). Human peripheral blood ILC2s were isolated from total PBMCs as described previously 42 . Briefly, human fresh blood was first diluted 1:1 in PBS and transferred to SepMateTM-50 separation tubes (STEMCELL Technologies) prefilled with 15 mL LymphoprepTM (Axis-Shield).…”

Impact of a Demyelination-Inducing Central Nervous System Virus on Expression of Demyelination Genes in Type 2 Lymphoid Cells

“…ILC2s are involved in immune responses, inflammation, metabolic homeostasis, and tissue remodeling (35,(37)(38)(39)(40)(41)(42)(43). Their dysregulation leads to diseases such as asthma and dermatitis, and we previously showed that ILC2s play an important role in HSV-IL-2-induced demyelination in the CNS (47).…”

“…ILCs have protective roles against certain diseases and infections, while their dysregulated activation is linked to pathogenesis. Dysregulation of ILC2s has been implicated in the pathology of diseases including allergies, asthma, dermatitis, fibrosis, and type 2 diabetes (35,(37)(38)(39)(40)(41)(42)(43). ILC2s are present in the brain and can communicate with neurons by mediating the neuropeptide neuromedin U (NMU) in certain contexts (44)(45)(46).…”

c-Rel is required for IL-33-dependent activation of ILC2s

“…While the primary source of IL-33 is epithelial cells (2), other cell types such as NKT cells and alveolar macrophages (37) have also been shown to produce IL-33. Previous studies have established a role for several factors for a number of transcription factors such as GFI1 (38), ETS1 (39), TCF1 (40,41), G9a (32), and non-canonical NF-κB factors (22,42) as important regulators of ILC2 biology; however, the roles of canonical NF-κB proteins have not been directly examined in ILC2s. The present study identified the presence of canonical NF-κB family members p50, RelA and c-Rel activity in ILC2s in following IL-33 stimulation.…”

“…IL-33-ST2 signalling is also critical for ILC2 function, although whether NF-κB is required remains unclear (20,21). Recently, non-canonical NF-κB signalling has been shown to be required for IL-33-dependent ILC2s in adipose tissue following death receptor 3 engagement (22), as well as in pulmonary ILC2s upon tumour necrosis factor receptor 2 binding (23). However, adiponectin treatment used to activate the energy sensor AMP-activated protein kinase inhibits the phosphorylation of IKKα/β and IκBα in IL-33-activated adipose-resident ILC2s and impairs IL-13 production (24), suggesting that canonical NF-κB signalling may also play an important role in ILC2 activation and function.…”