DR3 Stimulation of Adipose Resident ILC2s Ameliorates Type 2 Diabetes Mellitus

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Sep 19

PMID 32948777

Citations 22

Authors

Pedram Shafiei-Jahani

Benjamin P Hurrell

Lauriane Galle-Treger

Doumet Georges Helou

Emily Howard

Jacob Painter

Richard Lo

Gavin Lewis

Pejman Soroosh

Omid Akbari

Affiliations

Soon will be listed here.

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.

Citing Articles

The role of fecal microbiota transplantation in type 2 diabetes mellitus treatment.

Wang H, Li S, Zhang L, Zhang N Front Endocrinol (Lausanne). 2024; 15:1469165.

PMID: 39735647 PMC: 11671274. DOI: 10.3389/fendo.2024.1469165.

CB2 stimulation of adipose resident ILC2s orchestrates immune balance and ameliorates type 2 diabetes mellitus.

Shafiei-Jahani P, Yan S, Kazemi M, Li X, Akbari A, Sakano K Cell Rep. 2024; 43(7):114434.

PMID: 38963763 PMC: 11317174. DOI: 10.1016/j.celrep.2024.114434.

TNF Superfamily and ILC2 Activation in Asthma.

Matsuyama T, Salter B, Fard N, Machida K, Sehmi R Biomolecules. 2024; 14(3).

PMID: 38540714 PMC: 10967788. DOI: 10.3390/biom14030294.

Adipose tissue aging is regulated by an altered immune system.

Zhang Y, Ou M, Yang Z, Sun Y, Li Q, Zhou S Front Immunol. 2023; 14:1125395.

PMID: 36875140 PMC: 9981968. DOI: 10.3389/fimmu.2023.1125395.

Cytokine-mediated immunomodulation of osteoclastogenesis.

Zhou P, Zheng T, Zhao B Bone. 2022; 164:116540.

PMID: 36031187 PMC: 10657632. DOI: 10.1016/j.bone.2022.116540.

References

Osborn O, Olefsky J . The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012; 18(3):363-74. DOI: 10.1038/nm.2627. View

Sun K, Kusminski C, Scherer P . Adipose tissue remodeling and obesity. J Clin Invest. 2011; 121(6):2094-101. PMC: 3104761. DOI: 10.1172/JCI45887. View

Molofsky A, Nussbaum J, Liang H, Van Dyken S, Cheng L, Mohapatra A . Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages. J Exp Med. 2013; 210(3):535-49. PMC: 3600903. DOI: 10.1084/jem.20121964. View

Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H . Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells. Nature. 2009; 463(7280):540-4. DOI: 10.1038/nature08636. View

Brestoff J, Kim B, Saenz S, Stine R, Monticelli L, Sonnenberg G . Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature. 2014; 519(7542):242-6. PMC: 4447235. DOI: 10.1038/nature14115. View

Odegaard J, Chawla A . Alternative macrophage activation and metabolism. Annu Rev Pathol. 2010; 6:275-97. PMC: 3381938. DOI: 10.1146/annurev-pathol-011110-130138. View

McLaren J, Calder C, McSharry B, Sexton K, Salter R, Singh N . The TNF-like protein 1A-death receptor 3 pathway promotes macrophage foam cell formation in vitro. J Immunol. 2010; 184(10):5827-34. PMC: 2874519. DOI: 10.4049/jimmunol.0903782. View

Meylan F, Davidson T, Kahle E, Kinder M, Acharya K, Jankovic D . The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity. 2008; 29(1):79-89. PMC: 2760084. DOI: 10.1016/j.immuni.2008.04.021. View

Twohig J, Marsden M, Cuff S, Ferdinand J, Gallimore A, Perks W . The death receptor 3/TL1A pathway is essential for efficient development of antiviral CD4⁺ and CD8⁺ T-cell immunity. FASEB J. 2012; 26(8):3575-86. PMC: 3460213. DOI: 10.1096/fj.11-200618. View

10.

Nishikii H, Kim B, Yokoyama Y, Chen Y, Baker J, Pierini A . DR3 signaling modulates the function of Foxp3+ regulatory T cells and the severity of acute graft-versus-host disease. Blood. 2016; 128(24):2846-2858. PMC: 5159706. DOI: 10.1182/blood-2016-06-723783. View

11.

Yu X, Pappu R, Ramirez-Carrozzi V, Ota N, Caplazi P, Zhang J . TNF superfamily member TL1A elicits type 2 innate lymphoid cells at mucosal barriers. Mucosal Immunol. 2013; 7(3):730-40. PMC: 3998636. DOI: 10.1038/mi.2013.92. View

12.

Meylan F, Hawley E, Barron L, Barlow J, Penumetcha P, Pelletier M . The TNF-family cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells. Mucosal Immunol. 2013; 7(4):958-68. PMC: 4165592. DOI: 10.1038/mi.2013.114. View

13.

Heidemann S, Chavez V, Landers C, Kucharzik T, Prehn J, Targan S . TL1A selectively enhances IL-12/IL-18-induced NK cell cytotoxicity against NK-resistant tumor targets. J Clin Immunol. 2010; 30(4):531-8. PMC: 2900590. DOI: 10.1007/s10875-010-9382-9. View

14.

Ahn Y, Weeres M, Neulen M, Choi J, Kang S, Heo D . Human group3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation. Eur J Immunol. 2015; 45(8):2335-42. PMC: 4595159. DOI: 10.1002/eji.201445213. View

15.

Twohig J, Roberts M, Gavalda N, Rees-Taylor E, Giralt A, Adams D . Age-dependent maintenance of motor control and corticostriatal innervation by death receptor 3. J Neurosci. 2010; 30(10):3782-92. PMC: 2880713. DOI: 10.1523/JNEUROSCI.1928-09.2010. View

16.

Jacob N, Jacobs J, Kumagai K, Ha C, Kanazawa Y, Lagishetty V . Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome. Mucosal Immunol. 2018; 11(5):1466-1476. PMC: 6162160. DOI: 10.1038/s41385-018-0055-y. View

17.

Al-Lamki R, Wang J, Tolkovsky A, Bradley J, Griffin J, Thiru S . TL1A both promotes and protects from renal inflammation and injury. J Am Soc Nephrol. 2008; 19(5):953-60. PMC: 2386725. DOI: 10.1681/ASN.2007060706. View

18.

Al-Lamki R, Lu W, Finlay S, Twohig J, Wang E, Tolkovsky A . DR3 signaling protects against cisplatin nephrotoxicity mediated by tumor necrosis factor. Am J Pathol. 2012; 180(4):1454-64. DOI: 10.1016/j.ajpath.2012.01.003. View

19.

Wang E . On death receptor 3 and its ligands…. Immunology. 2012; 137(1):114-6. PMC: 3449252. DOI: 10.1111/j.1365-2567.2012.03606.x. View

20.

Valatas V, Kolios G, Bamias G . TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity. Front Immunol. 2019; 10:583. PMC: 6445966. DOI: 10.3389/fimmu.2019.00583. View