TNFR2 Signaling Enhances ILC2 Survival, Function, and Induction of Airway Hyperreactivity

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2019 Dec 26

PMID 31875557

Citations 37

Authors

Benjamin P Hurrell

Lauriane Galle-Treger

Pedram Shafiei Jahani

Emily Howard

Doumet Georges Helou

Homayon Banie

Pejman Soroosh

Omid Akbari

Affiliations

Soon will be listed here.

Abstract

Group 2 innate lymphoid cells (ILC2s) can initiate pathologic inflammation in allergic asthma by secreting copious amounts of type 2 cytokines, promoting lung eosinophilia and airway hyperreactivity (AHR), a cardinal feature of asthma. We discovered that the TNF/TNFR2 axis is a central immune checkpoint in murine and human ILC2s. ILC2s selectively express TNFR2, and blocking the TNF/TNFR2 axis inhibits survival and cytokine production and reduces ILC2-dependent AHR. The mechanism of action of TNFR2 in ILC2s is through the non-canonical NF-κB pathway as an NF-κB-inducing kinase (NIK) inhibitor blocks the costimulatory effect of TNF-α. Similarly, human ILC2s selectively express TNFR2, and using hILC2s, we show that TNFR2 engagement promotes AHR through a NIK-dependent pathway in alymphoid murine recipients. These findings highlight the role of the TNF/TNFR2 axis in pulmonary ILC2s, suggesting that targeting TNFR2 or relevant signaling is a different strategy for treating patients with ILC2-dependent asthma.

Citing Articles

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References

Nagashima H, Okuyama Y, Fujita T, Takeda T, Motomura Y, Moro K . GITR cosignal in ILC2s controls allergic lung inflammation. J Allergy Clin Immunol. 2018; 141(5):1939-1943.e8. DOI: 10.1016/j.jaci.2018.01.028. View

Cai Y, Cao Y, Lu S, Xu C, Cardell L . Infliximab alleviates inflammation and ex vivo airway hyperreactivity in asthmatic E3 rats. Int Immunol. 2011; 23(7):443-51. DOI: 10.1093/intimm/dxr032. View

Taille C, Poulet C, Marchand-Adam S, Borie R, Dombret M, Crestani B . Monoclonal Anti-TNF-α Antibodies for Severe Steroid-Dependent Asthma: A Case Series. Open Respir Med J. 2013; 7:21-5. PMC: 3601337. DOI: 10.2174/1874306401307010021. View

Aggarwal B . Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol. 2003; 3(9):745-56. DOI: 10.1038/nri1184. View

Howarth P, Babu K, Arshad H, Lau L, Buckley M, McConnell W . Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax. 2005; 60(12):1012-8. PMC: 1747263. DOI: 10.1136/thx.2005.045260. View

Hasegawa A, Takasaki W, Greene M, Murali R . Modifying TNFalpha for therapeutic use: a perspective on the TNF receptor system. Mini Rev Med Chem. 2002; 1(1):5-16. DOI: 10.2174/1389557013407214. View

Galle-Treger L, Sankaranarayanan I, Hurrell B, Howard E, Lo R, Maazi H . Costimulation of type-2 innate lymphoid cells by GITR promotes effector function and ameliorates type 2 diabetes. Nat Commun. 2019; 10(1):713. PMC: 6372786. DOI: 10.1038/s41467-019-08449-x. View

Bartemes K, Iijima K, Kobayashi T, Kephart G, Mckenzie A, Kita H . IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol. 2011; 188(3):1503-13. PMC: 3262877. DOI: 10.4049/jimmunol.1102832. View

Brightbill H, Suto E, Blaquiere N, Ramamoorthi N, Sujatha-Bhaskar S, Gogol E . NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus. Nat Commun. 2018; 9(1):179. PMC: 5766581. DOI: 10.1038/s41467-017-02672-0. View

10.

Malaviya R, Laskin J, Laskin D . Anti-TNFα therapy in inflammatory lung diseases. Pharmacol Ther. 2017; 180:90-98. PMC: 5693260. DOI: 10.1016/j.pharmthera.2017.06.008. View

11.

Bunting M, Shadie A, Flesher R, Nikiforova V, Garthwaite L, Tedla N . Interleukin-33 drives activation of alveolar macrophages and airway inflammation in a mouse model of acute exacerbation of chronic asthma. Biomed Res Int. 2013; 2013:250938. PMC: 3722780. DOI: 10.1155/2013/250938. View

12.

Anticevich S, Hughes J, Black J, Armour C . Induction of human airway hyperresponsiveness by tumour necrosis factor-alpha. Eur J Pharmacol. 1995; 284(1-2):221-5. DOI: 10.1016/0014-2999(95)00463-u. View

13.

Vieira S, Lemos H, Grespan R, Napimoga M, Dal-Secco D, Freitas A . A crucial role for TNF-alpha in mediating neutrophil influx induced by endogenously generated or exogenous chemokines, KC/CXCL1 and LIX/CXCL5. Br J Pharmacol. 2009; 158(3):779-89. PMC: 2765597. DOI: 10.1111/j.1476-5381.2009.00367.x. View

14.

Mortier J, Masereel B, Remouchamps C, Ganeff C, Piette J, Frederick R . NF-kappaB inducing kinase (NIK) inhibitors: identification of new scaffolds using virtual screening. Bioorg Med Chem Lett. 2010; 20(15):4515-20. DOI: 10.1016/j.bmcl.2010.06.027. View

15.

Berry M, Hargadon B, Shelley M, Parker D, Shaw D, Green R . Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med. 2006; 354(7):697-708. DOI: 10.1056/NEJMoa050580. View

16.

Klein Wolterink R, Kleinjan A, van Nimwegen M, Bergen I, de Bruijn M, Levani Y . Pulmonary innate lymphoid cells are major producers of IL-5 and IL-13 in murine models of allergic asthma. Eur J Immunol. 2012; 42(5):1106-16. DOI: 10.1002/eji.201142018. View

17.

Pfoertner S, Jeron A, Probst-Kepper M, Guzman C, Hansen W, Westendorf A . Signatures of human regulatory T cells: an encounter with old friends and new players. Genome Biol. 2006; 7(7):R54. PMC: 1779567. DOI: 10.1186/gb-2006-7-7-r54. View

18.

Wang J, Ferreira R, Lu W, Farrow S, Downes K, Jermutus L . TNFR2 ligation in human T regulatory cells enhances IL2-induced cell proliferation through the non-canonical NF-κB pathway. Sci Rep. 2018; 8(1):12079. PMC: 6089958. DOI: 10.1038/s41598-018-30621-4. View

19.

Brightling C, Berry M, Amrani Y . Targeting TNF-alpha: a novel therapeutic approach for asthma. J Allergy Clin Immunol. 2007; 121(1):5-10. PMC: 3992375. DOI: 10.1016/j.jaci.2007.10.028. View

20.

Aggarwal B, Gupta S, Kim J . Historical perspectives on tumor necrosis factor and its superfamily: 25 years later, a golden journey. Blood. 2011; 119(3):651-65. PMC: 3265196. DOI: 10.1182/blood-2011-04-325225. View