{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T22:14:46Z","timestamp":1794003286667,"version":"4.8.0"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Idiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) is a severe autoimmune condition with limited treatment options. Phosphodiesterase 4B (PDE4B) is a key enzyme in the metabolism of cyclic adenosine monophosphate (cAMP) in lung tissue, and targeting PDE4B has been proposed as a promising therapeutic strategy. This study aimed to evaluate the therapeutic potential of Nerandomilast (a PDE4B inhibitor) in an experimental IIM-ILD model and to investigate its underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>An IIM-ILD mouse model was established by immunization with skeletal muscle homogenate. Mice were treated with Nerandomilast (5 or 12.5 mg\/kg, twice daily) or Nintedanib (60 mg\/kg, once daily) as a positive control. Disease severity was assessed using myositis scores and spleen index. Pulmonary fibrosis and inflammation were evaluated via micro-CT, histopathology, and bronchoalveolar lavage fluid (BALF) analysis. B cell infiltration, activation, and differentiation were examined by flow cytometry, immunofluorescence, and Western blotting. Key signaling pathways were analyzed in lung tissue.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Nerandomilast ameliorated muscle inflammation, pulmonary fibrosis, and pulmonary inflammation. Mechanistically, Nerandomilast targeted lung-infiltrating B cells: it inhibited their accumulation and proliferation, downregulated the activation marker BAFF, and suppressed their differentiation into plasma cells by reducing the expression of key transcription factors and the plasma cell marker. Serological testing indicated a significant decrease in anti-Jo-1 autoantibody positivity. At the molecular level, Nerandomilast elevated lung tissue cAMP levels, inhibited the phosphorylation of pro-survival\/activation pathways (PI3K\/AKT, NF-\u03baB, STAT3) in B cells, and enhanced CREB phosphorylation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The PDE4B inhibitor Nerandomilast demonstrates potent therapeutic effects in a preclinical IIM-ILD model, alleviating both myositis and pulmonary pathology. Its efficacy is mechanistically linked to the direct modulation of B cells, achieved by elevating intracellular cAMP and subsequently reprogramming key signaling networks to inhibit B cell activation, proliferation, and pathogenic differentiation into antibody-producing plasma cells. These findings highlight Nerandomilast as a promising candidate for the treatment of IIM-ILD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1771007","type":"journal-article","created":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T05:34:05Z","timestamp":1771392845000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Nerandomilast attenuates idiopathic inflammatory myopathy-associated interstitial lung disease via inhibiting proliferation and differentiation of B cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Yuming","family":"Liu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayue","family":"Hu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Molecular Drug Research","place":["Tianjin International Joint Academy of Biomedicine, Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Se-rigeleng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongyi","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueze","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayang","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Molecular Drug Research","place":["Tianjin International Joint Academy of Biomedicine, Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huihui","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Molecular Drug Research","place":["Tianjin International Joint Academy of Biomedicine, Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songtao","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Respiratory & Critical Care Medicine, Tianjin Chest Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weitao","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Xuchang Central Hospital","place":["Xuchang, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Molecular Drug Research","place":["Tianjin International Joint Academy of Biomedicine, Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honggang","family":"Zhou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Molecular Drug Research","place":["Tianjin International Joint Academy of Biomedicine, Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"He","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital of Zhengzhou University","place":["Zhengzhou, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyu","family":"Kong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Gu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Molecular Drug Research","place":["Tianjin International Joint Academy of Biomedicine, Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohe","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin First Central Hospital, Nankai University","place":["Tianjin, China"]},{"name":"Tianjin Key Laboratory of Molecular Drug Research","place":["Tianjin International Joint Academy of Biomedicine, Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics15030275","article-title":"Recognition of idiopathic inflammatory myopathies underlying interstitial lung diseases","volume":"15","author":"Morina","year":"2025","journal-title":"Diagnostics (Basel)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.eclinm.2024.102598","article-title":"FAPi PET\/CT for assessment and visualisation of active myositis-related interstitial lung disease: a prospective observational pilot study","volume":"72","author":"Kastrati","year":"2024","journal-title":"EClinicalMedicine"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00296-023-05302-9","article-title":"Rituximab as the first-line therapy in anti-synthetase syndrome-related interstitial lung disease","volume":"43","author":"Zeki\u0107","year":"2023","journal-title":"Rheumatol Int"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2023.152164","article-title":"Intravenous cyclophosphamide improves functional outcomes in interstitial lung disease related to idiopathic inflammatory myopathies","volume":"59","author":"Moreno-Torres","year":"2023","journal-title":"Semin Arthritis Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.978429","article-title":"The efficacy and safety of tacrolimus on top of glucocorticoids in the management of IIM-ILD: A retrospective and prospective study","volume":"13","author":"Chen","year":"2022","journal-title":"Front Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1177\/1759720X211060907","article-title":"Role of antifibrotics in the management of idiopathic inflammatory myopathy associated interstitial lung disease","volume":"13","author":"Wilfong","year":"2021","journal-title":"Ther Adv Musculoskelet Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2021.106581","article-title":"Diagnosis of myositis-associated interstitial lung disease: Utility of the myositis autoantibody line immunoassay","volume":"187","author":"Jee","year":"2021","journal-title":"Respir Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2022.152088","article-title":"The role of myositis-specific autoantibodies and the management of interstitial lung disease in idiopathic inflammatory myopathies: A systematic review","volume":"57","author":"Teel","year":"2022","journal-title":"Semin Arthritis Rheumatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e003121","DOI":"10.1136\/rmdopen-2023-003121","article-title":"Interstitial lung disease with and without progressive fibrosing phenotype in patients with idiopathic inflammatory myopathies: data from a large multicentric cohort","volume":"9","author":"Zanatta","year":"2023","journal-title":"RMD Open"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1019915","article-title":"Rituximab for the treatment of connective tissue disease-associated interstitial lung disease: A systematic review and meta-analysis","volume":"13","author":"Xu","year":"2022","journal-title":"Front Pharmacol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113313","article-title":"Zanubrutinib ameliorates experimental idiopathic inflammatory myopathy-associated interstitial lung disease by BTK\/NF-\u03baB signaling pathway","volume":"143","author":"Liu","year":"2024","journal-title":"Int Immunopharmacol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2414108","article-title":"Nerandomilast in patients with idiopathic pulmonary fibrosis","volume":"392","author":"Richeldi","year":"2025","journal-title":"N Engl J Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2503643","article-title":"Nerandomilast in patients with progressive pulmonary fibrosis","volume":"392","author":"Maher","year":"2025","journal-title":"N Engl J Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-024-02153-9","article-title":"Nerandomilast improves bleomycin-induced systemic sclerosis-associated interstitial lung disease in mice by regulating the TGF-\u03b21 pathway","volume":"48","author":"Liu","year":"2025","journal-title":"Inflammation"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/molecules30061311","article-title":"BI 1015550 improves silica-induced silicosis and LPS-induced acute lung injury in mice","volume":"30","author":"Liu","year":"2025","journal-title":"Molecules"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2024-0614OC","article-title":"Insights into the Cellular and Molecular Mechanisms behind the Antifibrotic Effects of Nerandomilast","volume":"73","author":"Reininger","year":"2025","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/bph.17303","article-title":"PDE4B inhibition by nerandomilast: Effects on lung fibrosis and transcriptome in fibrotic rats and on biomarkers in human lung epithelial cells","volume":"181","author":"Reininger","year":"2024","journal-title":"Br J Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70240","article-title":"Nerandomilast, a PDE4B inhibitor, alleviates silica-induced lung inflammation and fibrosis by inhibition of NLRP3 inflammasome and TGF-\u03b2\/Smad signalling","author":"Wang","year":"2025","journal-title":"Br J Pharmacol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"220206","DOI":"10.1183\/16000617.0206-2022","article-title":"Phosphodiesterase 4B inhibition: a potential novel strategy for treating pulmonary fibrosis","volume":"32","author":"Kolb","year":"2023","journal-title":"Eur Respir Rev"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-019-0492-y","article-title":"Disruption of the Myc-PDE4B regulatory circuitry impairs B-cell lymphoma survival","volume":"33","author":"Nam","year":"2019","journal-title":"Leukemia"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004-01-0240","article-title":"The phosphodiesterase PDE4B limits cAMP-associated PI3K\/AKT-dependent apoptosis in diffuse large B-cell lymphoma","volume":"105","author":"Smith","year":"2005","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2008.091405","article-title":"Increased serum levels of B cell activating factor (BAFF) in subsets of patients with idiopathic inflammatory myopathies","volume":"68","author":"Krystufkov\u00e1","year":"2009","journal-title":"Ann Rheum Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.21.120601.141138","article-title":"Regulatory mechanisms that determine the development and function of plasma cells","volume":"21","author":"Calame","year":"2003","journal-title":"Annu Rev Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s40164-020-00191-1","article-title":"Complex roles of cAMP-PKA-CREB signaling in cancer","volume":"9","author":"Zhang","year":"2020","journal-title":"Exp Hematol Oncol"},{"key":"B25","article-title":"IL-6\/STAT3 signaling pathway is activated in plasma cell mastitis","volume":"8","author":"Liu","year":"2015","journal-title":"Int J Clin Exp Pathol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1771007\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T11:31:07Z","timestamp":1771932667000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1771007\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,18]]},"references-count":25,"alternative-id":["10.3389\/fimmu.2026.1771007"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1771007","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,18]]},"article-number":"1771007"}}