{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:04:40Z","timestamp":1785423880880,"version":"3.56.0"},"reference-count":77,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005762","name":"National Taiwan University Hospital","doi-asserted-by":"publisher","award":["NTUHYL 110.S021"],"award-info":[{"award-number":["NTUHYL 110.S021"]}],"id":[{"id":"10.13039\/501100005762","id-type":"DOI","asserted-by":"publisher"}]},{"award":["NTUHYL 110.S021"],"award-info":[{"award-number":["NTUHYL 110.S021"]}],"id":[{"id":"https:\/\/ror.org\/03nteze27","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Science and Technology Council","award":["NSTC 113-2314-B-567-001"],"award-info":[{"award-number":["NSTC 113-2314-B-567-001"]}]},{"name":"National Science and Technology Council","award":["NSTC 113-2320-B-002-010-MY3"],"award-info":[{"award-number":["NSTC 113-2320-B-002-010-MY3"]}]},{"award":["NSTC 113-2314-B-567-001"],"award-info":[{"award-number":["NSTC 113-2314-B-567-001"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NSTC 113-2320-B-002-010-MY3"],"award-info":[{"award-number":["NSTC 113-2320-B-002-010-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Decoy receptor 3 (DcR3) is a pleiotropic soluble factor that modulates cellular functions through both decoy and non-decoy mechanisms. DcR3 has been reported to exert anti-apoptotic and anti-inflammatory effects in humans, particularly in cancers and inflammatory diseases. In the present study, we investigated the role of DcR3 in TLR4-mediated innate immune responses in macrophages. Because the DcR3 gene is absent in the mouse genome, we generated myeloid-specific DcR3 knock-in mice and isolated bone marrow-derived macrophages (BMDMs) for functional analyses. Our results showed that DcR3 did not significantly affect LPS-induced expression of COX-2, iNOS, NLRP3, or pro-IL-1\u03b2. Aggresome-like induced structures (ALIS), which consist of aggregates of ubiquitinated proteins, are stress-induced cytoplasmic compartments implicated in MHC class I antigen presentation. We found that DcR3 suppressed LPS-induced ALIS formation by attenuating cellular reactive oxygen species production and p38 MAPK activation. In addition to LPS stimulation, DcR3 also reduced the accumulation of ubiquitinated proteins induced by HO-1 inhibitor ZnPP, lysosomal inhibitor bafilomycin A1, and proteasomal inhibitor MG132. Consistent with a role for autophagy in ALIS regulation, rapamycin reduced LPS-induced ALIS formation, whereas bafilomycin A1 induced comparable LC3-II accumulation in both wild-type and DcR3-expressing macrophages. Furthermore, DcR3 expression did not significantly alter LPS-induced p62 or HO-1 expression. Collectively, although DcR3 does not markedly influence LPS-induced inflammatory responses in BMDMs, our findings reveal a previously unrecognized role for DcR3 in suppressing ALIS formation and the accumulation of ubiquitinated proteins in macrophages, thereby suggesting a novel function for DcR3 in maintaining intracellular protein homeostasis under stress conditions.<\/jats:p>","DOI":"10.3390\/ijms27146433","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DcR3 Suppresses Lipopolysaccharide-Induced Aggresome-like Structures in Macrophages via Inhibition of Reactive Oxygen Species and p38 MAPK"],"prefix":"10.3390","volume":"27","author":[{"given":"Chun-Hung","family":"Lee","sequence":"first","affiliation":[{"name":"Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duen-Yi","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shie-Liang","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"},{"name":"Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan"},{"name":"Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112201, Taiwan"},{"name":"Department of Microbiology and Immunology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Shen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, National Taiwan University Hospital Yunlin Branch, Douliu 64041, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3207-734X","authenticated-orcid":false,"given":"Wan-Wan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.str.2010.12.004","article-title":"Decoy strategies: The structure of TL1A:DcR3 complex","volume":"19","author":"Zhan","year":"2011","journal-title":"Structure"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1016\/j.str.2016.09.009","article-title":"Crystal Structure of the Complex of Human FasL and Its Decoy Receptor DcR3","volume":"24","author":"Liu","year":"2016","journal-title":"Structure"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.bcp.2011.01.011","article-title":"Decoy receptor 3: A pleiotropic immunomodulator and biomarker for inflammatory diseases, autoimmune diseases and cancer","volume":"81","author":"Lin","year":"2011","journal-title":"Biochem. 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