Melissa Y Tjota1, Cara L Hrusch2, Kelly M Blaine2, Jesse W Williams3, Nora A Barrett4, Anne I Sperling5. 1. Committee on Immunology, University of Chicago, Chicago, Ill; Medical Scientist Training Program, University of Chicago, Chicago, Ill. 2. Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Ill. 3. Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, Ill. 4. Department of Medicine, Division of Rheumatology, Immunology, and Allergy, Harvard Medical School, Boston, Mass. 5. Committee on Immunology, University of Chicago, Chicago, Ill; Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Ill; Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, Ill. Electronic address: asperlin@uchicago.edu.
Abstract
BACKGROUND: Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown. OBJECTIVE: We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation. METHODS: C57BL/6, FcγRIII(-/-), FcRγ(-/-), and ST2(-/-) mice were sensitized and challenged with HDM, and inflammation was assessed based on results of flow cytometry and histology and cytokine production. Bone marrow-derived DCs from these strains were used in signaling and adoptive transfer experiments. RESULTS: Our findings indicate that 2 distinct TH2 stimuli, ICs and HDM, use the FcRγ-associated receptors FcγRIII and Dectin-2, respectively, to promote TH2-mediated lung inflammation. In this study we demonstrate that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of TH2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcRγ, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of TH2 responses in FcRγ-deficient mice. Finally, adoptive transfer of allergen-pulsed FcRγ(+/-) bone-marrow derived DCs restores the development of TH2-type inflammation in FcRγ-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation. CONCLUSION: These data identify a mechanism whereby TH2 stimuli signal through FcRγ-associated receptors on DCs to upregulate IL-33 production and induce TH2-mediated allergic airway inflammation.
BACKGROUND: Although allergic sensitization can be generated against various allergens, it is unknown how such a diversity of antigens is able to promote TH2-mediated inflammation leading to atopy. Our previous studies demonstrated that allergen-specific IgG immune complexes (ICs) and house dust mite (HDM) extract both induced dendritic cells (DCs) to drive TH2-mediated inflammation, but the mechanism by which these diverse stimuli produce similar responses is unknown. OBJECTIVE: We sought to identify the DC signaling pathways used by TH2 stimuli to promote TH2-mediated inflammation. METHODS: C57BL/6, FcγRIII(-/-), FcRγ(-/-), and ST2(-/-) mice were sensitized and challenged with HDM, and inflammation was assessed based on results of flow cytometry and histology and cytokine production. Bone marrow-derived DCs from these strains were used in signaling and adoptive transfer experiments. RESULTS: Our findings indicate that 2 distinct TH2 stimuli, ICs and HDM, use the FcRγ-associated receptors FcγRIII and Dectin-2, respectively, to promote TH2-mediated lung inflammation. In this study we demonstrate that both ICs and HDM induce expression of IL-33, a critical mediator in asthma pathogenesis and the differentiation of TH2 cells, in DCs. Upregulation of IL-33 in DCs is dependent on FcRγ, Toll-like receptor 4, and phosphoinositide 3-kinase. Exogenous IL-33 is sufficient to restore the development of TH2 responses in FcRγ-deficient mice. Finally, adoptive transfer of allergen-pulsed FcRγ(+/-) bone-marrow derived DCs restores the development of TH2-type inflammation in FcRγ-deficient mice, demonstrating the necessity of this signaling pathway in DCs for allergen-induced inflammation. CONCLUSION: These data identify a mechanism whereby TH2 stimuli signal through FcRγ-associated receptors on DCs to upregulate IL-33 production and induce TH2-mediated allergic airway inflammation.
Authors: Jesse W Williams; Melissa Y Tjota; Bryan S Clay; Bryan Vander Lugt; Hozefa S Bandukwala; Cara L Hrusch; Donna C Decker; Kelly M Blaine; Bethany R Fixsen; Harinder Singh; Roger Sciammas; Anne I Sperling Journal: Nat Commun Date: 2013 Impact factor: 14.919
Authors: Néomi S Grotenboer; Maria E Ketelaar; Gerard H Koppelman; Martijn C Nawijn Journal: J Allergy Clin Immunol Date: 2013-02-04 Impact factor: 10.793
Authors: Daniel Rittirsch; Michael A Flierl; Danielle E Day; Brian A Nadeau; Firas S Zetoune; J Vidya Sarma; Clement M Werner; Guido A Wanner; Hans-Peter Simmen; Markus S Huber-Lang; Peter A Ward Journal: PLoS Pathog Date: 2009-06-05 Impact factor: 6.823
Authors: Tess L Killpack; Maria Ballesteros; Stephen C Bunnell; Alice Bedugnis; Lester Kobzik; Linden T Hu; Tanja Petnicki-Ocwieja Journal: Infect Immun Date: 2017-09-20 Impact factor: 3.441
Authors: Li-Yin Hung; Yukinori Tanaka; Karl Herbine; Christopher Pastore; Brenal Singh; Annabel Ferguson; Nisha Vora; Bonnie Douglas; Kelly Zullo; Edward M Behrens; Tiffany Li Hui Tan; Michael A Kohanski; Paul Bryce; Cailu Lin; Taku Kambayashi; Danielle R Reed; Breann L Brown; Noam A Cohen; De'Broski R Herbert Journal: Sci Immunol Date: 2020-11-13
Authors: Li-Yin Hung; Taylor K Oniskey; Debasish Sen; Matthew F Krummel; Andrew E Vaughan; Noam A Cohen; De'Broski R Herbert Journal: Am J Pathol Date: 2018-02-16 Impact factor: 4.307