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DR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus

Author

Listed:
  • 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)

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.

Suggested Citation

  • Pedram Shafiei-Jahani & Benjamin P. Hurrell & Lauriane Galle-Treger & Doumet Georges Helou & Emily Howard & Jacob Painter & Richard Lo & Gavin Lewis & Pejman Soroosh & Omid Akbari, 2020. "DR3 stimulation of adipose resident ILC2s ameliorates type 2 diabetes mellitus," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18601-7
    DOI: 10.1038/s41467-020-18601-7
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