DR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus.
Pedram Shafiei-JahaniBenjamin P HurrellLauriane Galle-TregerDoumet Georges HelouEmily HowardJacob D PainterRichard LoGavin LewisPejman SorooshOmid AkbariPublished in: Nature communications (2020)
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.
Keyphrases
- insulin resistance
- adipose tissue
- editorial comment
- metabolic syndrome
- low grade
- nk cells
- high fat diet
- glycemic control
- peripheral blood
- skeletal muscle
- type diabetes
- oxidative stress
- high fat diet induced
- high grade
- signaling pathway
- rheumatoid arthritis
- poor prognosis
- induced apoptosis
- mouse model
- cell proliferation
- uric acid
- binding protein
- blood pressure
- cell death
- social media
- lps induced
- combination therapy
- pi k akt
- drug induced