{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T16:10:27Z","timestamp":1784045427306,"version":"3.55.0"},"reference-count":117,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,23]],"date-time":"2021-11-23T00:00:00Z","timestamp":1637625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011771","name":"Vascular Medicine Institute, University of Pittsburgh","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011771","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["P01 HL114453, R01 HL136143, R01 HL142084, K24 HL143285, R01 HL123515581"],"award-info":[{"award-number":["P01 HL114453, R01 HL136143, R01 HL142084, K24 HL143285, R01 HL123515581"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The IL-36 family of cytokines were identified in the early 2000\u2019s as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2021.754702","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T14:00:35Z","timestamp":1638280835000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Interleukin-36 Cytokines in Infectious and Non-Infectious Lung Diseases"],"prefix":"10.3389","volume":"12","author":[{"given":"Hern\u00e1n F.","family":"Pe\u00f1aloza","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick","family":"van der Geest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel A.","family":"Ybe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore J.","family":"Standiford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet S.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12610","article-title":"Regulation and Function of Interleukin-36 Cytokines","volume":"281","author":"Bassoy","year":"2018","journal-title":"Immunol Rev"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s1471-4906(01)02034-8","article-title":"Annotating Genes With Potential Roles in the Immune System: Six New Members of the IL-1 Family","volume":"22","author":"Dunn","year":"2001","journal-title":"Trends Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2002.6751","article-title":"A Sequence-Based Map of the Nine Genes of the Human Interleukin-1 Cluster","volume":"79","author":"Nicklin","year":"2002","journal-title":"Genomics"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2002.6752","article-title":"Genomic Organization of the Interleukin-1 Locus","volume":"79","author":"Taylor","year":"2002","journal-title":"Genomics"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.14.10308","article-title":"Identification and Initial Characterization of Four Novel Members of the Interleukin-1 Family","volume":"275","author":"Kumar","year":"2000","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6184","article-title":"Identification and Gene Organization of Three Novel Members of the IL-1 Family on Human Chromosome 2","volume":"66","author":"Busfield","year":"2000","journal-title":"Genomics"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.2.1169","article-title":"Four New Members Expand the Interleukin-1 Superfamily","volume":"275","author":"Smith","year":"2000","journal-title":"J Biol Chem"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.3.1440","article-title":"Two Novel IL-1 Family Members, IL-1 Delta and IL-1 Epsilon, Function as an Antagonist and Agonist of NF-Kappa B Activation Through the Orphan IL-1 Receptor-Related Protein 2","volume":"167","author":"Debets","year":"2001","journal-title":"J Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1038\/ni1110-973","article-title":"IL-1 Family Nomenclature","volume":"11","author":"Dinarello","year":"2010","journal-title":"Nat Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/s1471-4906(01)02040-3","article-title":"A New Nomenclature for IL-1-Family Genes","volume":"22","author":"Sims","year":"2001","journal-title":"Trends Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400117200","article-title":"Interleukin (IL)-1f6, IL-1F8, and IL-1f9 Signal Through IL-1Rrp2 and IL-1racp to Activate the Pathway Leading to NF-kappaB and MAPKs","volume":"279","author":"Towne","year":"2004","journal-title":"J Biol Chem"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.12.7727","article-title":"The Interleukin-1 Receptor Accessory Protein (IL-1racp) Is Essential for IL-1-Induced Activation of Interleukin-1 Receptor-Associated Kinase (IRAK) and Stress-Activated Protein Kinases (SAP Kinases)","volume":"272","author":"Wesche","year":"1997","journal-title":"J Biol Chem"},{"key":"B13","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/s0065-2776(08)60535-0","article-title":"Interleukin-1 Receptor Antagonist","volume":"54","author":"Arend","year":"1993","journal-title":"Adv Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.267922","article-title":"Interleukin-36 (IL-36) Ligands Require Processing for Full Agonist (IL-36alpha, IL-36beta, and IL-36gamma) or Antagonist (IL-36ra) Activity","volume":"286","author":"Towne","year":"2011","journal-title":"J Biol Chem"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01162","article-title":"Interleukin-36 in Infectious and Inflammatory Skin Diseases","volume":"10","author":"Buhl","year":"2019","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the Human Tissue-Specific Expression by Genome-Wide Integration of Transcriptomics and Antibody-Based Proteomics","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol Cell Proteomics"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.07.820","article-title":"IL-36gamma Induced by the TLR3-SLUG-VDR Axis Promotes Wound Healing via REG3A","volume":"137","author":"Jiang","year":"2017","journal-title":"J Invest Dermatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI63451","article-title":"Psoriasiform Dermatitis is Driven by IL-36-Mediated DC-Keratinocyte Crosstalk","volume":"122","author":"Tortola","year":"2012","journal-title":"J Clin Invest"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.00955","article-title":"IL-36gamma Augments Host Defense and Immune Responses in Human Female Reproductive Tract Epithelial Cells","volume":"7","author":"Winkle","year":"2016","journal-title":"Front Microbiol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501263","article-title":"IRF6 Regulates the Expression of IL-36gamma by Human Oral Epithelial Cells in Response to Porphyromonas Gingivalis","volume":"196","author":"Huynh","year":"2016","journal-title":"J Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010-0075OC","article-title":"Regulation and Function of the IL-1 Family Cytokine IL-1F9 in Human Bronchial Epithelial Cells","volume":"45","author":"Chustz","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.4A0315-087R","article-title":"IL-36gamma is Secreted in Microparticles and Exosomes by Lung Macrophages in Response to Bacteria and Bacterial Components","volume":"100","author":"Kovach","year":"2016","journal-title":"J Leukoc Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1800515","article-title":"IL-36 and IL-1\/IL-17 Drive Immunity to Oral Candidiasis via Parallel Mechanisms","volume":"201","author":"Verma","year":"2018","journal-title":"J Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ejphar.2016.11.013","article-title":"Role of Pathogen-Associated Molecular Patterns (PAMPS) in Immune Responses to Fungal Infections","volume":"808","author":"Taghavi","year":"2017","journal-title":"Eur J Pharmacol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0138423","article-title":"Interleukin (IL)-1beta Is a Strong Inducer of IL-36gamma Expression in Human Colonic Myofibroblasts","volume":"10","author":"Takahashi","year":"2015","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.385443","article-title":"IL-36gamma\/IL-1F9, an Innate T-Bet Target in Myeloid Cells","volume":"287","author":"Bachmann","year":"2012","journal-title":"J Biol Chem"},{"key":"B27","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/sj.cdd.4401189","article-title":"Tumor Necrosis Factor Signaling","volume":"10","author":"Wajant","year":"2003","journal-title":"Cell Death Differ"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2010.06.004","article-title":"IL-17 and IL-22: Siblings, Not Twins","volume":"31","author":"Eyerich","year":"2010","journal-title":"Trends Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aan3589","article-title":"Interleukin-36 Cytokines may Overcome Microbial Immune Evasion Strategies That Inhibit Interleukin-1 Family Signaling","volume":"10","author":"Jensen","year":"2017","journal-title":"Sci Signal"},{"key":"B30","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.cyto.2015.06.017","article-title":"The Interleukin (IL)-1 Cytokine Family\u2013Balance Between Agonists and Antagonists in Inflammatory Diseases","volume":"76","author":"Palomo","year":"2015","journal-title":"Cytokine"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-018-0486-y","article-title":"Comprehensive Network Map of Interferon Gamma Signaling","volume":"12","author":"Bhat","year":"2018","journal-title":"J Cell Commun Signal"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.261570598","article-title":"T-Bet is Rapidly Induced by Interferon-Gamma in Lymphoid and Myeloid Cells","volume":"98","author":"Lighvani","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2016.5","article-title":"T-Bet Expression by Th Cells Promotes Type 1 Inflammation But Is Dispensable for Colitis","volume":"9","author":"Zimmermann","year":"2016","journal-title":"Mucosal Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.05.054","article-title":"T-Bet Activates Th1 Genes Through Mediator and the Super Elongation Complex","volume":"15","author":"Hertweck","year":"2016","journal-title":"Cell Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501447","article-title":"Autocrine and Paracrine Regulation of Keratinocyte Proliferation Through a Novel Nrf2-IL-36gamma Pathway","volume":"196","author":"Kurinna","year":"2016","journal-title":"J Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.12.072","article-title":"Neutrophil-Derived Proteases Escalate Inflammation Through Activation of IL-36 Family Cytokines","volume":"14","author":"Henry","year":"2016","journal-title":"Cell Rep"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.02.062","article-title":"Extracellular Neutrophil Proteases Are Efficient Regulators of IL-1, IL-33, and IL-36 Cytokine Activity But Poor Effectors of Microbial Killing","volume":"22","author":"Clancy","year":"2018","journal-title":"Cell Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/srep24880","article-title":"Neutrophil Elastase-Mediated Proteolysis Activates the Anti-Inflammatory Cytokine IL-36 Receptor Antagonist","volume":"6","author":"Macleod","year":"2016","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620954114","article-title":"Cathepsin S Is the Major Activator of the Psoriasis-Associated Proinflammatory Cytokine IL-36gamma","volume":"114","author":"Ainscough","year":"2017","journal-title":"Proc Natl Acad Sci USA"},{"key":"B40","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/s41419-018-0385-4","article-title":"Suppressing IL-36-Driven Inflammation Using Peptide Pseudosubstrates for Neutrophil Proteases","volume":"9","author":"Sullivan","year":"2018","journal-title":"Cell Death Dis"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.03336-20","article-title":"Thrombospondin-1 Restricts Interleukin-36gamma-Mediated Neutrophilic Inflammation During Pseudomonas Aeruginosa Pulmonary Infection","volume":"12","author":"Pe\u00f1aloza","year":"2021","journal-title":"mBio"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01523-2018","article-title":"Targeting of Cathepsin S Reduces Cystic Fibrosis-Like Lung Disease","volume":"53","author":"Small","year":"2019","journal-title":"Eur Respir J"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.3.1205","article-title":"Cathepsin S Controls MHC Class II-Mediated Antigen Presentation by Epithelial Cells In Vivo","volume":"174","author":"Beers","year":"2005","journal-title":"J Immunol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.biochi.2019.03.013","article-title":"Imaging of Extracellular Cathepsin S Activity by a Selective Near Infrared Fluorescence Substrate-Based Probe","volume":"166","author":"Wartenberg","year":"2019","journal-title":"Biochimie"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108515","article-title":"The Proinflammatory Cytokine IL-36gamma Is a Global Discriminator of Harmless Microbes and Invasive Pathogens Within Epithelial Tissues","volume":"33","author":"Macleod","year":"2020","journal-title":"Cell Rep"},{"key":"B46","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1038\/mi.2014.120","article-title":"Thrombospondin-1 Restrains Neutrophil Granule Serine Protease Function and Regulates the Innate Immune Response During Klebsiella Pneumoniae Infection","volume":"8","author":"Zhao","year":"2015","journal-title":"Mucosal Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.96914","article-title":"Thrombospondin-1 Protects Against Pathogen-Induced Lung Injury by Limiting Extracellular Matrix Proteolysis","volume":"3","author":"Qu","year":"2018","journal-title":"JCI Insight"},{"key":"B48","doi-asserted-by":"publisher","first-page":"3318","DOI":"10.3390\/ijms20133318","article-title":"The Significance of IL-36 Hyperactivation and IL-36r Targeting in Psoriasis","volume":"20","author":"Madonna","year":"","journal-title":"Int J Mol Sci"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301481","article-title":"IL-36 Promotes Myeloid Cell Infiltration, Activation, and Inflammatory Activity in Skin","volume":"192","author":"Foster","year":"2014","journal-title":"J Immunol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.cyto.2016.05.023","article-title":"IL-36 Receptor Is Expressed by Human Blood and Intestinal T Lymphocytes and is Dose-Dependently Activated via IL-36beta and Induces CD4+ Lymphocyte Proliferation","volume":"85","author":"Penha","year":"2016","journal-title":"Cytokine"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2017.12.972","article-title":"The Activation and Function of IL-36gamma in Neutrophilic Inflammation in Chronic Rhinosinusitis","volume":"141","author":"Wang","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-05-356873","article-title":"IL-36r Ligands Are Potent Regulators of Dendritic and T Cells","volume":"118","author":"Vigne","year":"2011","journal-title":"Blood"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.23.13757","article-title":"Molecular Cloning and Characterization of a Second Subunit of the Interleukin 1 Receptor Complex","volume":"270","author":"Greenfeder","year":"1995","journal-title":"J Biol Chem"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.805739","article-title":"Quantitative Ligand and Receptor Binding Studies Reveal the Mechanism of Interleukin-36 (IL-36) Pathway Activation","volume":"293","author":"Zhou","year":"2018","journal-title":"J Biol Chem"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1121534109","article-title":"IL-38 Binds to the IL-36 Receptor and has Biological Effects on Immune Cells Similar to IL-36 Receptor Antagonist","volume":"109","author":"van de Veerdonk","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.723064","article-title":"Structural and Functional Attributes of the Interleukin-36 Receptor","volume":"291","author":"Yi","year":"2016","journal-title":"J Biol Chem"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1400538","article-title":"Molecular Determinants of Agonist and Antagonist Signaling Through the IL-36 Receptor","volume":"193","author":"Gunther","year":"2014","journal-title":"J Immunol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2014.156","article-title":"Inflammation: IL-36 has Proinflammatory Effects in Skin But Not in Joints","volume":"10","author":"Dietrich","year":"2014","journal-title":"Nat Rev Rheumatol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00080","article-title":"RNA-Seq Analysis of IL-1B and IL-36 Responses in Epidermal Keratinocytes Identifies a Shared MyD88-Dependent Gene Signature","volume":"9","author":"Swindell","year":"2018","journal-title":"Front Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1801377115","article-title":"IkappaBzeta Is a Key Transcriptional Regulator of IL-36-Driven Psoriasis-Related Gene Expression in Keratinocytes","volume":"115","author":"Muller","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2011.234","article-title":"Inter-Regulation of Th17 Cytokines and the IL-36 Cytokines In Vitro and In Vivo: Implications in Psoriasis Pathogenesis","volume":"131","author":"Carrier","year":"2011","journal-title":"J Invest Dermatol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1718902115","article-title":"A Cytokine Network Involving IL-36gamma, IL-23, and IL-22 Promotes Antimicrobial Defense and Recovery From Intestinal Barrier Damage","volume":"115","author":"Ngo","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2004484117","article-title":"IL-36r Signaling Integrates Innate and Adaptive Immune-Mediated Protection Against Enteropathogenic Bacteria","volume":"117","author":"Ngo","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016080840","article-title":"IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23\/IL-17 Axis in Renal Inflammation and Fibrosis","volume":"28","author":"Chi","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-439026","article-title":"IL-36 Signaling Amplifies Th1 Responses by Enhancing Proliferation and Th1 Polarization of Naive CD4+ T Cells","volume":"120","author":"Vigne","year":"2012","journal-title":"Blood"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.21","article-title":"IL-36gamma Signaling Controls the Induced Regulatory T Cell-Th9 Cell Balance via NFkappaB Activation and STAT Transcription Factors","volume":"10","author":"Harusato","year":"2017","journal-title":"Mucosal Immunol"},{"key":"B67","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.ccell.2015.07.014","article-title":"IL-36gamma Transforms the Tumor Microenvironment and Promotes Type 1 Lymphocyte-Mediated Antitumor Immune Responses","volume":"28","author":"Wang","year":"2015","journal-title":"Cancer Cell"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiw152","article-title":"Role of Interleukin 36gamma in Host Defense Against Tuberculosis","volume":"214","author":"Ahsan","year":"2016","journal-title":"J Infect Dis"},{"key":"B69","doi-asserted-by":"publisher","first-page":"1520","DOI":"10.1038\/s41598-018-19476-x","article-title":"IL-36\/LXR Axis Modulates Cholesterol Metabolism and Immune Defense to Mycobacterium Tuberculosis","volume":"8","author":"Ahsan","year":"2018","journal-title":"Sci Rep"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1701796","article-title":"IL-36gamma Protects Against Severe Influenza Infection by Promoting Lung Alveolar Macrophage Survival and Limiting Viral Replication","volume":"201","author":"Wein","year":"2018","journal-title":"J Immunol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00583-18","article-title":"Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense Against Murine Legionella Pneumophila Pneumonia","volume":"87","author":"Nanjo","year":"2019","journal-title":"Infect Immun"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro.2017.14","article-title":"The Microbiota of the Respiratory Tract: Gatekeeper to Respiratory Health","volume":"15","author":"Man","year":"2017","journal-title":"Nat Rev Microbiol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0045784","article-title":"IL-36alpha Exerts Pro-Inflammatory Effects in the Lungs of Mice","volume":"7","author":"Ramadas","year":"2012","journal-title":"PloS One"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2009-0315OC","article-title":"Interleukin-1 Family Member 9 Stimulates Chemokine Production and Neutrophil Influx in Mouse Lungs","volume":"44","author":"Ramadas","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2016.130","article-title":"IL-36gamma is a Crucial Proximal Component of Protective Type-1-Mediated Lung Mucosal Immunity in Gram-Positive and -Negative Bacterial Pneumonia","volume":"10","author":"Kovach","year":"2017","journal-title":"Mucosal Immunol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0126058","article-title":"Limited Contribution of IL-36 Versus IL-1 and TNF Pathways in Host Response to Mycobacterial Infection","volume":"10","author":"Segueni","year":"2015","journal-title":"PloS One"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1006737","article-title":"Interleukin-36gamma and IL-36 Receptor Signaling Mediate Impaired Host Immunity and Lung Injury in Cytotoxic Pseudomonas Aeruginosa Pulmonary Infection: Role of Prostaglandin E2","volume":"13","author":"Aoyagi","year":"2017","journal-title":"PloS Pathog"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2016.107","article-title":"IL-36 Receptor Deletion Attenuates Lung Injury and Decreases Mortality in Murine Influenza Pneumonia","volume":"10","author":"Aoyagi","year":"2017","journal-title":"Mucosal Immunol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60216-0","article-title":"Community-Acquired Pneumonia","volume":"371","author":"Garau","year":"2008","journal-title":"Lancet"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1097\/MJT.0000000000000551","article-title":"Antimicrobial Resistant Streptococcus Pneumoniae: Prevalence, Mechanisms, and Clinical Implications","volume":"24","author":"Cherazard","year":"2017","journal-title":"Am J Ther"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2016.08.030","article-title":"Emergence of Antibiotic-Resistant non-Vaccine Serotype Pneumococci in Nasopharyngeal Carriage in Children After the Use of Extended-Valency Pneumococcal Conjugate Vaccines in Korea","volume":"34","author":"Choe","year":"2016","journal-title":"Vaccine"},{"key":"B82","doi-asserted-by":"publisher","first-page":"8127","DOI":"10.1038\/s41598-017-08717-0","article-title":"Rapid Replacement by Non-Vaccine Pneumococcal Serotypes may Mitigate the Impact of the Pneumococcal Conjugate Vaccine on Nasopharyngeal Bacterial Ecology","volume":"7","author":"Kwambana-Adams","year":"2017","journal-title":"Sci Rep"},{"key":"B83","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1038\/nrmicro1871","article-title":"The Role of Streptococcus Pneumoniae Virulence Factors in Host Respiratory Colonization and Disease","volume":"6","author":"Kadioglu","year":"2008","journal-title":"Nat Rev Microbiol"},{"key":"B84","doi-asserted-by":"publisher","first-page":"51","DOI":"10.2174\/156652313804806615","article-title":"Gene Elements That Regulate Streptococcus Pneumoniae Virulence and Immunity Evasion","volume":"13","author":"Nieto","year":"2013","journal-title":"Curr Gene Ther"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1128\/iai.65.7.2975-2977.1997","article-title":"Role of Gamma Interferon in the Pathogenesis of Bacteremic Pneumococcal Pneumonia","volume":"65","author":"Rubins","year":"1997","journal-title":"Infect Immun"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.13.6954","article-title":"Superoxide and Peroxynitrite Generation From Inducible Nitric Oxide Synthase in Macrophages","volume":"94","author":"Xia","year":"1997","journal-title":"Proc Natl Acad Sci USA"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.00078-15","article-title":"Klebsiella Pneumoniae: Going on the Offense With a Strong Defense","volume":"80","author":"Paczosa","year":"2016","journal-title":"Microbiol Mol Biol Rev"},{"key":"B88","doi-asserted-by":"publisher","first-page":"e00693\u201320","DOI":"10.1128\/IAI.00693-20","article-title":"Finding Order in the Chaos: Outstanding Questions in Klebsiella Pneumoniae Pathogenesis","volume":"89","author":"Gonzalez-Ferrer","year":"","journal-title":"Infect Immun"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3201\/eid2011.131872","article-title":"Legionnaires\u2019 Disease Incidence and Risk Factors, New York, New York, USA, 2002-2011","volume":"20","author":"Farnham","year":"2014","journal-title":"Emerg Infect Dis"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)70713-3","article-title":"Epidemiology and Clinical Management of Legionnaires\u2019 Disease","volume":"14","author":"Phin","year":"2014","journal-title":"Lancet Infect Dis"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.2807\/ese.18.10.20417-en","article-title":"Legionnaires Disease in Europe, 2009-2010","volume":"18","author":"Beaute","year":"2013","journal-title":"Euro Surveill"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000268","article-title":"Legionella: Virulence Factors and Host Response","volume":"29","author":"Misch","year":"2016","journal-title":"Curr Opin Infect Dis"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1172\/JCI35288","article-title":"Liver X Receptors Contribute to the Protective Immune Response Against Mycobacterium Tuberculosis in Mice","volume":"119","author":"Korf","year":"2009","journal-title":"J Clin Invest"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/j.diagmicrobio.2017.06.009","article-title":"Multidrug-Resistant Pseudomonas Aeruginosa Lower Respiratory Tract Infections in the Intensive Care Unit: Prevalence and Risk Factors","volume":"89","author":"Trinh","year":"2017","journal-title":"Diagn Microbiol Infect Dis"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2011.00155","article-title":"Protein Secretion Systems in Pseudomonas Aeruginosa: An Essay on Diversity, Evolution, and Function","volume":"2","author":"Filloux","year":"2011","journal-title":"Front Microbiol"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636636","article-title":"Bacterial Clearance of Pseudomonas Aeruginosa is Enhanced by the Inhibition of COX-2","volume":"37","author":"Sadikot","year":"2007","journal-title":"Eur J Immunol"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2005.00635.x","article-title":"Eicosanoid-Mediated Proinflammatory Activity of Pseudomonas Aeruginosa ExoU","volume":"7","author":"Saliba","year":"2005","journal-title":"Cell Microbiol"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.106200","article-title":"Interleukin-36 Receptor Antagonist Alleviates Airway Inflammation in Asthma via Inhibiting the Activation of Interleukin-36 Pathway","volume":"81","author":"Liu","year":"2020","journal-title":"Int Immunopharmacol"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-019-0300-7","article-title":"Anti-Inflammatory Mechanisms of the Novel Cytokine Interleukin-38 in Allergic Asthma","volume":"17","author":"Sun","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1016\/j.resinv.2017.06.001","article-title":"Overexpression of IL-38 Protein in Anticancer Drug-Induced Lung Injury and Acute Exacerbation of Idiopathic Pulmonary Fibrosis","volume":"55","author":"Tominaga","year":"2017","journal-title":"Respir Investig"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2008.0139","article-title":"Distinct Regulatory Profiles of Interleukins and Chemokines in Response to Cigarette Smoke Condensate in Normal Human Bronchial Epithelial (NHBE) Cells","volume":"28","author":"Parsanejad","year":"2008","journal-title":"J Interferon Cytokine Res"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2020-0035OC","article-title":"IL-36 Cytokines Promote Inflammation in the Lungs of Long-Term Smokers","volume":"64","author":"Kovach","year":"2020","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.87168","article-title":"Antiinflammatory Effects of Bromodomain and Extraterminal Domain Inhibition in Cystic Fibrosis Lung Inflammation","volume":"1","author":"Chen","year":"2016","journal-title":"JCI Insight"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181598","article-title":"Clinical Implications of the Novel Cytokine IL-38 Expressed in Lung Adenocarcinoma: Possible Association With PD-L1 Expression","volume":"12","author":"Takada","year":"2017","journal-title":"PloS One"},{"key":"B105","doi-asserted-by":"publisher","first-page":"1082","DOI":"10.1053\/j.gastro.2018.11.029","article-title":"Inhibiting Interleukin 36 Receptor Signaling Reduces Fibrosis in Mice With Chronic Intestinal Inflammation","volume":"156","author":"Scheibe","year":"2019","journal-title":"Gastroenterology"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1111\/crj.13338","article-title":"Elevated Sputum IL-36 Levels are Associated With Neutrophil-Related Inflammation in COPD Patients","volume":"15","author":"Li","year":"2021","journal-title":"Clin Respir J"},{"key":"B107","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s12967-017-1193-9","article-title":"Cystic Fibrosis: Current Therapeutic Targets and Future Approaches","volume":"15","author":"Rafeeq","year":"2017","journal-title":"J Transl Med"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01910-2017","article-title":"Elastase Activity on Sputum Neutrophils Correlates With Severity of Lung Disease in Cystic Fibrosis","volume":"51","author":"Dittrich","year":"2018","journal-title":"Eur Respir J"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-013-1471-1","article-title":"Decreased Expression of Interleukin-36alpha Correlates With Poor Prognosis in Hepatocellular Carcinoma","volume":"62","author":"Pan","year":"2013","journal-title":"Cancer Immunol Immunother"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X17735756","article-title":"Anti-Interleukin and Interleukin Therapies for Psoriasis: Current Evidence and Clinical Usefulness","volume":"9","author":"Tsai","year":"2017","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMc1811317","article-title":"Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis","volume":"380","author":"Bachelez","year":"2019","journal-title":"N Engl J Med"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2020.1746520","article-title":"Preclinical Characterization of the ADME Properties of a Surrogate Anti-IL-36r Monoclonal Antibody Antagonist in Mouse Serum and Tissues","volume":"12","author":"Conner","year":"2020","journal-title":"MAbs"},{"key":"B113","doi-asserted-by":"publisher","first-page":"896","DOI":"10.4161\/mabs.26436","article-title":"Effects of Altered FcgammaR Binding on Antibody Pharmacokinetics in Cynomolgus Monkeys","volume":"5","author":"Leabman","year":"2013","journal-title":"MAbs"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0467-1","article-title":"IL-1r3 Blockade Broadly Attenuates the Functions of Six Members of the IL-1 Family, Revealing Their Contribution to Models of Disease","volume":"20","author":"Hojen","year":"2019","journal-title":"Nat Immunol"},{"key":"B115","doi-asserted-by":"publisher","first-page":"9089","DOI":"10.1038\/s41598-019-45626-w","article-title":"Small Molecule IL-36gamma Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis","volume":"9","author":"Todorovic","year":"2019","journal-title":"Sci Rep"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.05.051","article-title":"Expression of SARS-CoV-2 Receptor ACE2 and Coincident Host Response Signature Varies by Asthma Inflammatory Phenotype","volume":"146","author":"Camiolo","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb2762","article-title":"Structural Basis for the Recognition of SARS-CoV-2 by Full-Length Human Ace2","volume":"367","author":"Yan","year":"2020","journal-title":"Science"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.754702\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T14:00:39Z","timestamp":1638280839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.754702\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,23]]},"references-count":117,"alternative-id":["10.3389\/fimmu.2021.754702"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.754702","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,23]]},"article-number":"754702"}}