Kentaro Machida1, Michael Aw2, Brittany Ma Salter2, Xiaotian Ju2, Manali Mukherjee3, Gail M Gauvreau2, Paul M O'Byrne2, Parameswaran Nair4, Roma Sehmi5. 1. Kagoshima University Medical and Dental Hospital, 163607, Kagoshima, Japan. 2. McMaster University, 3710, Medicine, Hamilton, Ontario, Canada. 3. McMaster University, 3710, Medicine, St Joseph's Healthcare, Hamilton, Ontario, Canada. 4. McMaster University, 3710, Medicine, St. Joseph's Healthcare, Hamilton, Ontario, Canada. 5. McMaster University, 3710, Medicine, Hamilton, Ontario, Canada; sehmir@mcmaster.ca.
Abstract
RATIONALE: Group 2 innate lymphoid cells (ILC2s) are critical for type 2 inflammation. In murine models of asthma, some ILC2s remain activated in the absence of epithelial-derived cytokine signaling, implicating alternate stimulatory pathways. Death receptor 3 (DR3), a member of the tumor necrosis factor receptor superfamily is expressed on ILC2s and genome wide association studies report an association between DR3 ligand, TNF like protein 1A (TL1A), and chronic inflammatory conditions. OBJECTIVES: We investigated the TL1A/DR3 axis in airway ILC2 biology in eosinophilic asthma. METHODS: Stable mild asthmatics were subject to allergen inhalation challenge and DR3 expression on sputum cells was assessed. We investigated cytokine regulation of DR3 expression on ILC2s and steroid sensitivity. Airway TL1A was assessed in sputum from mild asthmatics and prednisone-dependent severe eosinophilic asthmatics. MEASUREMENTS AND MAIN RESULTS: There was a significant increase in sputum DR3+ILC2s, 24 h post-allergen and in in vitro, DR3 expression on ILC2s was up-regulated by IL-2, IL-33 or TSLP. Stimulation with TL1A significantly increased IL-5 expression by ILC2s and attenuated by dexamethasone; an effect that was negated in the presence of TSLP. Airway TL1A levels were increased 24 h post-allergen challenge in mild asthmatics, but were significantly greater in severe eosinophilic asthmatics. The highest levels detected in severe asthmatics with airway autoimmune responses. C1q+ immune complexes from severe asthmatic sputa with high autoantibody levels stimulated TL1A production by monocytes. CONCLUSIONS: The TL1A/DR3 axis is a co-stimulator of ILC2s in asthma, particularly in the airways of patients with a predisposition to autoimmune responses.
RATIONALE: Group 2 innate lymphoid cells (ILC2s) are critical for type 2 inflammation. In murine models of asthma, some ILC2s remain activated in the absence of epithelial-derived cytokine signaling, implicating alternate stimulatory pathways. Death receptor 3 (DR3), a member of the tumor necrosis factor receptor superfamily is expressed on ILC2s and genome wide association studies report an association between DR3 ligand, TNF like protein 1A (TL1A), and chronic inflammatory conditions. OBJECTIVES: We investigated the TL1A/DR3 axis in airway ILC2 biology in eosinophilic asthma. METHODS: Stable mild asthmatics were subject to allergen inhalation challenge and DR3 expression on sputum cells was assessed. We investigated cytokine regulation of DR3 expression on ILC2s and steroid sensitivity. Airway TL1A was assessed in sputum from mild asthmatics and prednisone-dependent severe eosinophilic asthmatics. MEASUREMENTS AND MAIN RESULTS: There was a significant increase in sputum DR3+ILC2s, 24 h post-allergen and in in vitro, DR3 expression on ILC2s was up-regulated by IL-2, IL-33 or TSLP. Stimulation with TL1A significantly increased IL-5 expression by ILC2s and attenuated by dexamethasone; an effect that was negated in the presence of TSLP. Airway TL1A levels were increased 24 h post-allergen challenge in mild asthmatics, but were significantly greater in severe eosinophilic asthmatics. The highest levels detected in severe asthmatics with airway autoimmune responses. C1q+ immune complexes from severe asthmatic sputa with high autoantibody levels stimulated TL1A production by monocytes. CONCLUSIONS: The TL1A/DR3 axis is a co-stimulator of ILC2s in asthma, particularly in the airways of patients with a predisposition to autoimmune responses.
Authors: Rana Herro; Haruka Miki; Gurupreet S Sethi; David Mills; Amit Kumar Mehta; Xinh-Xinh Nguyen; Carol Feghali-Bostwick; Marina Miller; David H Broide; Rachel Soloff; Michael Croft Journal: J Immunol Date: 2020-09-21 Impact factor: 5.422
Authors: Andrew J Halayko; Christopher D Pascoe; Jessica D Gereige; Michael C Peters; Robyn T Cohen; Prescott G Woodruff Journal: Am J Respir Crit Care Med Date: 2021-08-15 Impact factor: 21.405