{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:00:58Z","timestamp":1790614858613,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T00:00:00Z","timestamp":1632873600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Science and Technology, Taiwan","award":["MOST107-2320-B-214-003, MOST108-2320-B-214-004-MY2, and MOST 110-2320-B-214-006"],"award-info":[{"award-number":["MOST107-2320-B-214-003, MOST108-2320-B-214-004-MY2, and MOST 110-2320-B-214-006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Group A Streptococcus (GAS) causes invasive human diseases with the cytokine storm. Interleukin-33 (IL-33)\/suppression of tumorigenicity 2 (ST2) axis is known to drive TH2 response, while its effect on GAS infection is unclear. We used an air pouch model to examine the effect of the IL-33\/ST2 axis on GAS-induced necrotizing fasciitis. GAS infection induced IL-33 expression in wild-type (WT) C57BL\/6 mice, whereas the IL-33- and ST2-knockout mice had higher mortality rates, more severe skin lesions and higher bacterial loads in the air pouches than those of WT mice after infection. Surveys of infiltrating cells in the air pouch of GAS-infected mice at the early stage found that the number and cell viability of infiltrating cells in both gene knockout mice were lower than those of WT mice. The predominant effector cells in GAS-infected air pouches were neutrophils. Absence of the IL-33\/ST2 axis enhanced the expression of inflammatory cytokines, but not TH1 or TH2 cytokines, in the air pouch after infection. Using in vitro assays, we found that the IL-33\/ST2 axis not only enhanced neutrophil migration but also strengthened the bactericidal activity of both sera and neutrophils. These results suggest that the IL-33\/ST2 axis provided the protective effect on GAS infection through enhancing the innate immunity.<\/jats:p>","DOI":"10.3390\/ijms221910566","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T00:03:42Z","timestamp":1632960222000},"page":"10566","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["IL-33\/ST2 Axis Plays a Protective Effect in Streptococcus pyogenes Infection through Strengthening of the Innate Immunity"],"prefix":"10.3390","volume":"22","author":[{"given":"Chih-Feng","family":"Kuo","sequence":"first","affiliation":[{"name":"School of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"},{"name":"Department of Nursing, College of Medicine, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9325-8734","authenticated-orcid":false,"given":"Wei-Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 833401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Han","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, College of Medical Science and Technology, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsuan","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, College of Medical Science and Technology, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Chu","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Science, College of Medical Science and Technology, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Peng","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"},{"name":"The Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Tsao","sequence":"additional","affiliation":[{"name":"Department of Biological Science and Technology, College of Medical Science and Technology, I-Shou University, Kaohsiung City 824005, Taiwan"},{"name":"Department of Medical Laboratory Science, College of Medical Science and Technology, I-Shou University, Kaohsiung City 824005, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1128\/CMR.00101-13","article-title":"Disease manifestations and pathogenic mechanisms of group A Streptococcus","volume":"27","author":"Walker","year":"2014","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3247","DOI":"10.1002\/1521-4141(200011)30:11<3247::AID-IMMU3247>3.0.CO;2-D","article-title":"Host variation in cytokine responses to superantigens determine the severity of invasive group A streptococcal infection","volume":"30","author":"Chatellier","year":"2000","journal-title":"Eur. J. Immunol."},{"key":"ref_3","first-page":"404","article-title":"Soluble M1 protein of Streptococcus pyogenes triggers potent T cell activation","volume":"10","author":"Olin","year":"2008","journal-title":"Cell. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1111\/j.1469-0691.2011.03624.x","article-title":"Invasive group A streptococcal infections in adults, France (2006\u20132010)","volume":"18","author":"Plainvert","year":"2012","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.immuni.2005.09.015","article-title":"IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines","volume":"23","author":"Schmitz","year":"2005","journal-title":"Immunity"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nri2692","article-title":"Disease-associated functions of IL-33: The new kid in the IL-1 family","volume":"10","author":"Liew","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s12026-012-8283-9","article-title":"IL-33\/ST2 axis in inflammation and immunopathology","volume":"52","author":"Milovanovic","year":"2012","journal-title":"Immunol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1128\/IAI.02908-14","article-title":"Crucial and diverse role of the interleukin-33\/ST2 axis in infectious diseases","volume":"83","author":"Rostan","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Moussion, C., Ortega, N., and Girard, J.P. (2008). The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: A novel \u2018alarmin\u2019?. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003331"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6633","DOI":"10.4049\/jimmunol.166.11.6633","article-title":"A novel pathway regulating lipopolysaccharide-induced shock by ST2\/T1 via inhibition of Toll-like receptor 4 expression","volume":"166","author":"Sweet","year":"2001","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5802","DOI":"10.4049\/jimmunol.0904127","article-title":"ST2 negatively regulates TLR2 signaling, but is not required for bacterial lipoprotein-induced tolerance","volume":"184","author":"Liu","year":"2010","journal-title":"J. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.4049\/jimmunol.1003080","article-title":"The dual function cytokine IL-33 interacts with the transcription factor NF-\u03baB to dampen NF-\u03baB-stimulated gene transcription","volume":"187","author":"Ali","year":"2011","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/j.bbrc.2012.04.005","article-title":"Nuclear IL-33 is a transcriptional regulator of NF-\u03baB p65 and induces endothelial cell activation","volume":"421","author":"Choi","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9021","DOI":"10.1073\/pnas.0812690106","article-title":"The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1","volume":"106","author":"Cayrol","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.immuni.2009.05.007","article-title":"Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases","volume":"31","author":"Cullen","year":"2009","journal-title":"Immunity"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2601","DOI":"10.3389\/fimmu.2018.02601","article-title":"The pleiotropic immunomodulatory functions of IL-33 and its implications in tumor immunity","volume":"9","author":"Afferni","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1002\/j.1460-2075.1994.tb06367.x","article-title":"Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor","volume":"13","author":"Bergers","year":"1994","journal-title":"EMBO J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/nm.2156","article-title":"Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection","volume":"16","author":"Souto","year":"2010","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3931","DOI":"10.1128\/IAI.66.8.3931-3935.1998","article-title":"Role of streptococcal pyrogenic exotoxin B in the mouse model of group A streptococcal infection","volume":"66","author":"Kuo","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s00430-012-0241-6","article-title":"Synergistic effects of streptolysin S and streptococcal pyrogenic exotoxin B on the mouse model of group A streptococcal infection","volume":"201","author":"Hung","year":"2012","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6425","DOI":"10.1002\/jcp.26429","article-title":"Macrophage plasticity, polarization, and function in health and disease","volume":"233","author":"Mohammadian","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.3389\/fimmu.2019.01982","article-title":"IL-17, IL-27, and IL-33: A novel axis linked to immunological dysfunction during sepsis","volume":"10","author":"Morrow","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_23","first-page":"3","article-title":"Role of the IL-33-ST2 axis in sepsis","volume":"4","author":"Xu","year":"2017","journal-title":"Mil. Med. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.immuni.2018.02.002","article-title":"Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions","volume":"48","author":"Evrard","year":"2018","journal-title":"Immunity"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.immuni.2008.05.019","article-title":"Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii","volume":"29","author":"Dunay","year":"2008","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1097\/ACI.0000000000000090","article-title":"Type-2 innate lymphoid cells in human allergic disease","volume":"14","author":"Barlow","year":"2014","journal-title":"Curr. Opin. Allergy Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.2165\/11634180-000000000-00000","article-title":"Invasive group a streptococcal disease: Epidemiology, pathogenesis and management","volume":"72","author":"Steer","year":"2012","journal-title":"Drugs"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1097\/QCO.0b013e328332bbfe","article-title":"Group A streptococcal vaccines: Facts versus fantasy","volume":"22","author":"Steer","year":"2009","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.1086\/374800","article-title":"Protection against group A streptococcus by immunization with J8-diphtheria toxoid: Contribution of J8- and diphtheria toxoid-specific antibodies to protection","volume":"187","author":"Batzloff","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_30","first-page":"1","article-title":"Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease","volume":"25","author":"Gorton","year":"2016","journal-title":"Autoimmunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.imlet.2015.11.009","article-title":"The immunoprotective activity of interleukin-33 in mouse model of cecal ligation and puncture-induced sepsis","volume":"169","author":"Li","year":"2016","journal-title":"Immunol. Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1159\/000479836","article-title":"IL-33 attenuates sepsis by inhibiting IL-17 receptor signaling through upregulation of SOCS3","volume":"42","author":"Lv","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s00011-018-1144-9","article-title":"IL-33 attenuates mortality by promoting IFN-gamma production in sepsis","volume":"67","author":"Bao","year":"2018","journal-title":"Inflamm. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"962","DOI":"10.3389\/fimmu.2018.00962","article-title":"Interleukin-33 Receptor (ST2) deficiency improves the outcome of Staphylococcus aureus-induced septic arthritis","volume":"9","author":"Trevelin","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_35","first-page":"e124168","article-title":"Protection against Staphylococcus aureus bacteremia-induced mortality depends on ILC2s and eosinophils","volume":"4","author":"Krishack","year":"2019","journal-title":"JCI Insight"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/mi.2017.32","article-title":"Novel protective mechanism for interleukin-33 at the mucosal barrier during influenza-associated bacterial superinfection","volume":"11","author":"Robinson","year":"2018","journal-title":"Mucosal Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14919","DOI":"10.1038\/ncomms14919","article-title":"IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population","volume":"8","author":"Nascimento","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/path.5601","article-title":"Interleukin-33 improves local immunity during Gram-negative pneumonia by a combined effect on neutrophils and inflammatory monocytes","volume":"253","author":"Blok","year":"2021","journal-title":"J. Pathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s00441-017-2776-8","article-title":"Neutrophil chemotaxis","volume":"371","author":"Petri","year":"2018","journal-title":"Cell Tissue Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1002\/hep.25768","article-title":"Interleukin-33 is hepatoprotective during liver ischemia\/reperfusion in mice","volume":"56","author":"Sakai","year":"2012","journal-title":"Hepatology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1111\/j.1365-2958.2005.04527.x","article-title":"Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway","volume":"56","author":"Carlsson","year":"2005","journal-title":"Mol. Micribiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.bbrc.2005.11.078","article-title":"Streptococcal pyrogenic exotoxin B cleaves properdin and inhibits complement-mediated opsonophagocytosis","volume":"339","author":"Tsao","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1128\/IAI.01116-07","article-title":"Degradation of complement 3 by streptococcal pyrogenic exotoxin B inhibits complement activation and neutrophil opsonophagocytosis","volume":"76","author":"Kuo","year":"2008","journal-title":"Infect. Immun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"15854","DOI":"10.1074\/jbc.M113.469106","article-title":"Cysteine proteinase from Streptococcus pyogenes enables evasion of innate immunity via degradation of complement factors","volume":"288","author":"Ogawa","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4293","DOI":"10.4049\/jimmunol.1003872","article-title":"Increased susceptibility of ST2-deficient mice to polymicrobial sepsis is associated with an impaired bactericidal function","volume":"187","author":"Buckley","year":"2011","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5371","DOI":"10.1038\/s41598-019-41853-3","article-title":"Streptolysin S induces mitochondrial damage and macrophage death through inhibiting degradation of glycogen synthase kinase-3\u03b2 in Streptococcus pyogenes infection","volume":"9","author":"Tsao","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.bbrc.2016.04.010","article-title":"Upregulation of Interleukin-33 in obstructive renal injury","volume":"473","author":"Chen","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kuo, C.F., Tsao, N., Hsieh, I.C., Lin, Y.S., Wu, J.J., and Hung, Y.T. (2017). Immunization with a streptococcal multiple-epitope recombinant protein protects mice against invasive group A streptococcal infection. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174464"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1111\/j.1365-2672.2009.04487.x","article-title":"Inhibition of group A streptococcal infection by Melaleuca alternifolia (tea tree) oil concentrate in the murine model","volume":"108","author":"Tsao","year":"2010","journal-title":"J. Appl. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1189\/jlb.0513251","article-title":"Hv1 proton channels differentially regulate the pH of neutrophil and macrophage phagosomes by sustaining the production of phagosomal ROS that inhibit the delivery of vacuolar ATPases","volume":"95","author":"Nunes","year":"2014","journal-title":"J. Leukoc. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10566\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:07:35Z","timestamp":1760166455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10566"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,29]]},"references-count":50,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910566"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910566","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,29]]}}}