DR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus

Pedram Shafiei-Jahani, Benjamin P. Hurrell, Lauriane Galle-Treger, Doumet Georges Helou, Emily Howard, Jacob Painter, Richard Lo, Gavin Lewis, Pejman Soroosh and Omid Akbari ()
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Pedram Shafiei-Jahani: Keck School of Medicine, University of Southern California
Benjamin P. Hurrell: Keck School of Medicine, University of Southern California
Lauriane Galle-Treger: Keck School of Medicine, University of Southern California
Doumet Georges Helou: Keck School of Medicine, University of Southern California
Emily Howard: Keck School of Medicine, University of Southern California
Jacob Painter: Keck School of Medicine, University of Southern California
Richard Lo: Keck School of Medicine, University of Southern California
Gavin Lewis: Janssen Research and Development
Pejman Soroosh: Janssen Research and Development
Omid Akbari: Keck School of Medicine, University of Southern California

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18601-7

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