{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T15:14:40Z","timestamp":1793459680856,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,18]],"date-time":"2021-02-18T00:00:00Z","timestamp":1613606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Type 2 inflammation is found in most forms of asthma, which may co-exist with recurrent viral infections, bacterial colonization, and host cell death. These processes drive the accumulation of intracellular cyclic-di-nucleotides such as cyclic-di-GMP (CDG). Group 2 innate lymphoid cells (ILC2s) are critical drivers of type 2 lung inflammation during fungal allergen exposure in mice; however, it is unclear how CDG regulates lung ILC responses during lung inflammation. Here, we show that intranasal CDG induced early airway type 1 interferon (IFN) production and dramatically suppressed CD127+ST2+ ILC2s and type 2 lung inflammation during\n                    <jats:italic>Alternaria<\/jats:italic>\n                    and IL-33 exposure. Further, CD127\u2013ST2\u2013Thy1.2+ lung ILCs, which showed a transcriptomic signature consistent with ILC1s, were expanded and activated by CDG combined with either\n                    <jats:italic>Alternaria<\/jats:italic>\n                    or IL-33. CDG-mediated suppression of type 2 inflammation occurred independent of IL-18R, IL-12, and STAT6 but required the stimulator of interferon genes (STING) and type 1 IFN signaling. Thus, CDG potently suppresses ILC2-driven lung inflammation and promotes ILC1 responses. These results suggest potential therapeutic modulation of STING to suppress type 2 inflammation and\/or increase anti-viral responses during respiratory infections.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2021.618807","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T07:52:48Z","timestamp":1613807568000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Cyclic-di-GMP Induces STING-Dependent ILC2 to ILC1 Shift During Innate Type 2 Lung Inflammation"],"prefix":"10.3389","volume":"12","author":[{"given":"Kellen J.","family":"Cavagnero","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana H.","family":"Badrani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luay H.","family":"Naji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Amadeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthea S.","family":"Leng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lee Diego","family":"Lacasa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allyssa N.","family":"Strohm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha R.","family":"Renusch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanna S.","family":"Gasparian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor A.","family":"Doherty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/nature08636","article-title":"Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells","volume":"463","author":"Moro","year":"2010","journal-title":"Nature."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1038\/nature08900","article-title":"Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity","volume":"464","author":"Neill","year":"2010","journal-title":"Nature."},{"key":"B3","doi-asserted-by":"publisher","first-page":"11489","DOI":"10.1073\/pnas.1003988107","article-title":"Systemically dispersed innate IL-13-expressing cells in type 2 immunity","volume":"107","author":"Price","year":"2010","journal-title":"Proc Natl Acad Sci USA."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1016\/j.jaci.2019.07.018","article-title":"Unconventional ST2- and CD127-negative lung ILC2 populations are induced by the fungal allergen Alternaria alternata","volume":"144","author":"Cavagnero","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/1465-9921-13-35","article-title":"Bacteria in sputum of stable severe asthma and increased airway wall thickness","volume":"13","author":"Zhang","year":"2012","journal-title":"Respir Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2741","DOI":"10.1172\/JCI60325","article-title":"Asthma as a chronic disease of the innate and adaptive immune systems responding to viruses and allergens","volume":"122","author":"Holtzman","year":"2012","journal-title":"J Clin Invest."},{"key":"B7","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1038\/cr.2013.26","article-title":"Death at the airway epithelium in asthma","volume":"23","author":"Lambrecht","year":"2013","journal-title":"Cell Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1038\/ni.3558","article-title":"Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing","volume":"17","author":"Chen","year":"2016","journal-title":"Nat Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"8327","DOI":"10.1128\/JB.01079-06","article-title":"Cyclic di-GMP signaling in bacteria: recent advances and new puzzles","volume":"188","author":"Ryan","year":"2006","journal-title":"J Bacteriol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1038\/nature10429","article-title":"STING is a direct innate immune sensor of cyclic di-GMP","volume":"478","author":"Burdette","year":"2011","journal-title":"Nature."},{"key":"B11","doi-asserted-by":"publisher","first-page":"4122","DOI":"10.1128\/JB.00132-10","article-title":"Cyclic di-GMP signaling regulates invasion by Ehrlichia chaffeensis of human monocytes","volume":"192","author":"Kumagai","year":"2010","journal-title":"J Bacteriol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"6335","DOI":"10.1073\/pnas.1901051116","article-title":"Cyclic-di-GMP regulation promotes survival of a slow-replicating subpopulation of intracellular Salmonella Typhimurium","volume":"116","author":"Petersen","year":"2019","journal-title":"Proc Natl Acad Sci USA."},{"key":"B13","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nchembio.1521","article-title":"Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness","volume":"10","author":"Lolicato","year":"2014","journal-title":"Nat Chem Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3595","DOI":"10.1093\/nar\/gky146","article-title":"HpoR, a novel c-di-GMP effective transcription factor, links the second messenger's regulatory function to the mycobacterial antioxidant defense","volume":"46","author":"Li","year":"2018","journal-title":"Nucl Acids Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"8330","DOI":"10.1038\/ncomms9330","article-title":"Cyclic diguanylate monophosphate directly binds to human siderocalin and inhibits its antibacterial activity","volume":"6","author":"Li","year":"2015","journal-title":"Nat Commun."},{"key":"B16","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1159\/000492679","article-title":"Cyclic dimeric guanosine monophosphate: activation and inhibition of innate immune response","volume":"11","author":"Cui","year":"2019","journal-title":"J Innate Immun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"17","DOI":"10.7554\/eLife.06670.017","article-title":"The mucosal adjuvant cyclic di-GMP enhances antigen uptake and selectively activates pinocytosis-efficient cells in vivo","volume":"4","author":"Blaauboer","year":"2015","journal-title":"Elife"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1899","DOI":"10.1084\/jem.20082874","article-title":"A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP","volume":"206","author":"Mcwhirter","year":"2009","journal-title":"J Exp Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced host response to SARS-CoV-2 drives development of COVID-19","volume":"181","author":"Blanco-Melo","year":"2020","journal-title":"Cell."},{"key":"B20","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/s41577-020-0335-0","article-title":"Impaired interferon signature in severe COVID-19","volume":"20","author":"Gruber","year":"2020","journal-title":"Nat Rev Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.chom.2020.07.005","article-title":"Retrospective multicenter cohort study shows early interferon therapy is associated with favorable clinical responses in COVID-19 patients","volume":"28","author":"Wang","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B22","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/j.chom.2020.04.017","article-title":"Heightened innate immune responses in the respiratory tract of COVID-19 patients","volume":"27","author":"Zhou","year":"2020","journal-title":"Cell Host Microbe."},{"key":"B23","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.immuni.2015.05.019","article-title":"Interleukin-33 and interferon-\u03b3 counter-regulate group 2 innate lymphoid cell activation during immune perturbation","volume":"43","author":"Molofsky","year":"2015","journal-title":"Immunity."},{"key":"B24","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/ni.3308","article-title":"Type I interferon restricts type 2 immunopathology through the regulation of group 2 innate lymphoid cells","volume":"17","author":"Duerr","year":"2016","journal-title":"Nat Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/mi.2017.41","article-title":"IFN-\u03b3 increases susceptibility to influenza A infection through suppression of group II innate lymphoid cells","volume":"11","author":"Califano","year":"2018","journal-title":"Mucosal Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"L577","DOI":"10.1152\/ajplung.00174.2012","article-title":"STAT6 regulates natural helper cell proliferation during lung inflammation initiated by Alternaria","volume":"303","author":"Doherty","year":"2012","journal-title":"Am J Physiol Lung Cell Mol Physiol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1111\/imr.12708","article-title":"New insights into the function, development, and plasticity of type 2 innate lymphoid cells","volume":"286","author":"Krabbendam","year":"2018","journal-title":"Immunol Rev."},{"key":"B28","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/ni.2182","article-title":"Divergent expression patterns of IL-4 and IL-13 define unique functions in allergic immunity","volume":"13","author":"Liang","year":"2011","journal-title":"Nat Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/nature12526","article-title":"Type 2 innate lymphoid cells control eosinophil homeostasis","volume":"502","author":"Nussbaum","year":"2013","journal-title":"Nature."},{"key":"B30","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1111\/imr.12547","article-title":"Are ILC2s Jekyll and Hyde in airway inflammation?","volume":"278","author":"Ealey","year":"2017","journal-title":"Immunol Rev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.4049\/jimmunol.1102832","article-title":"IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs","volume":"188","author":"Bartemes","year":"2012","journal-title":"J Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/ni.3443","article-title":"Inflammatory triggers associated with exacerbations of COPD orchestrate plasticity of group 2 innate lymphoid cells in the lungs","volume":"17","author":"Silver","year":"2016","journal-title":"Nat Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1016\/j.cell.2011.09.022","article-title":"Activation of STAT6 by STING is critical for antiviral innate immunity","volume":"147","author":"Chen","year":"2011","journal-title":"Cell."},{"key":"B34","doi-asserted-by":"publisher","first-page":"2622","DOI":"10.4049\/jimmunol.1101632","article-title":"Alternaria induces STAT6-dependent acute airway eosinophilia and epithelial FIZZ1 expression that promotes airway fibrosis and epithelial thickness","volume":"188","author":"Doherty","year":"2012","journal-title":"J Immunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/ni.3309","article-title":"Interferon and IL-27 antagonize the function of group 2 innate lymphoid cells and type 2 innate immune responses","volume":"17","author":"Moro","year":"2016","journal-title":"Nat Immunol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/cea.12585","article-title":"Autophagy mechanisms in sputum and peripheral blood cells of patients with severe asthma: a new therapeutic target","volume":"46","author":"Ban","year":"2016","journal-title":"Clin Exp Allergy."},{"key":"B37","doi-asserted-by":"publisher","first-page":"116","DOI":"10.4172\/2576-3881.1000116","article-title":"Cytokine and lipid mediator regulation of group 2 innate lymphoid cells (ILC2s) in human allergic airway disease","volume":"2","author":"Cavagnero","year":"2017","journal-title":"J Cytokine Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/nri3921","article-title":"STING: infection, inflammation and cancer","volume":"15","author":"Barber","year":"2015","journal-title":"Nat Rev Immunol."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2394","DOI":"10.1172\/JCI84144","article-title":"Current concepts of severe asthma","volume":"126","author":"Ray","year":"2016","journal-title":"J Clin Invest."},{"key":"B40","doi-asserted-by":"publisher","first-page":"5226","DOI":"10.1038\/s41467-018-07425-1","article-title":"STING-dependent sensing of self-DNA drives silica-induced lung inflammation","volume":"9","author":"Benmerzoug","year":"2018","journal-title":"Nat Commun."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1735","DOI":"10.1038\/s41418-018-0251-z","article-title":"STING directly activates autophagy to tune the innate immune response","volume":"26","author":"Liu","year":"2018","journal-title":"Cell Death Differ"},{"key":"B42","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1038\/s41586-019-1006-9","article-title":"Autophagy induction via STING trafficking is a primordial function of the cGAS pathway","volume":"567","author":"Gui","year":"2019","journal-title":"Nature."},{"key":"B43","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/ni.2491","article-title":"STING and the innate immune response to nucleic acids in the cytosol","volume":"14","author":"Burdette","year":"2013","journal-title":"Nat Immunol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"5328","DOI":"10.1128\/JVI.00037-14","article-title":"Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-\u03baB activation through TBK1","volume":"88","author":"Abe","year":"2014","journal-title":"J Virol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2101","DOI":"10.1016\/j.jid.2017.03.041","article-title":"STING is involved in antiviral immune response against VZV infection via the induction of type I and III IFN pathways","volume":"137","author":"Kim","year":"2017","journal-title":"J Invest Dermatol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.molcel.2018.07.034","article-title":"Non-canonical activation of the DNA sensing adaptor STING by ATM and IFI16 mediates NF-\u03baB signaling after nuclear DNA damage","volume":"71","author":"Dunphy","year":"2018","journal-title":"Mol Cell."},{"key":"B47","doi-asserted-by":"publisher","first-page":"e0197596","DOI":"10.1371\/journal.pone.0197596","article-title":"Interferon lambda is required for interferon gamma-expressing NK cell responses but does not afford antiviral protection during acute and persistent murine cytomegalovirus infection","volume":"13","author":"Gimeno Brias","year":"2018","journal-title":"PLoS ONE."},{"key":"B48","doi-asserted-by":"publisher","first-page":"2061","DOI":"10.3389\/fimmu.2018.02061","article-title":"The dual nature of type I and type II interferons","volume":"9","author":"Lee","year":"2018","journal-title":"Front Immunol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"3037","DOI":"10.1172\/JCI80911","article-title":"High IFN-\u03b3 and low SLPI mark severe asthma in mice and humans","volume":"125","author":"Raundhal","year":"2015","journal-title":"J Clin Invest."},{"key":"B50","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1038\/mi.2017.88","article-title":"The cytosolic sensor STING is required for intestinal homeostasis and control of inflammation","volume":"11","author":"Canesso","year":"2018","journal-title":"Mucosal Immunol."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1038\/s41590-018-0201-4","article-title":"Tissue signals imprint ILC2 identity with anticipatory function","volume":"19","author":"Ricardo-Gonzalez","year":"2018","journal-title":"Nat Immunol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.jaci.2019.01.044","article-title":"STING-associated lung disease in mice relies on T cells but not type I interferon","volume":"144","author":"Luksch","year":"2019","journal-title":"J Allergy Clin Immunol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.cytogfr.2014.08.004","article-title":"Message in a bottle: lessons learned from antagonism of STING signalling during RNA virus infection","volume":"25","author":"Maringer","year":"2014","journal-title":"Cytokine Growth Factor Rev."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e30802","DOI":"10.1371\/journal.pone.0030802","article-title":"Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling","volume":"7","author":"Sun","year":"2012","journal-title":"PLoS ONE."},{"key":"B55","doi-asserted-by":"publisher","first-page":"2696","DOI":"10.1073\/pnas.1518240113","article-title":"Contraction of the type I IFN locus and unusual constitutive expression of IFN-\u03b1 in bats","volume":"113","author":"Zhou","year":"2016","journal-title":"Proc Natl Acad Sci USA."},{"key":"B56","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.chom.2018.01.006","article-title":"Dampened STING-dependent interferon activation in bats","volume":"23","author":"Xie","year":"2018","journal-title":"Cell Host Microbe."},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1101\/2020.10.19.345850","article-title":"Cyclic-di-GMP induces STING-dependent ILC2 to ILC1 shift during innate type 2 lung inflammation","author":"Cavagnero","year":"2020","journal-title":"bioRxiv"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.618807\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T07:52:51Z","timestamp":1613807571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.618807\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,18]]},"references-count":57,"alternative-id":["10.3389\/fimmu.2021.618807"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.618807","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.10.19.345850","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,18]]},"article-number":"618807"}}