{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:43:51Z","timestamp":1791607431925,"version":"4.3.4"},"reference-count":36,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,19]],"date-time":"2026-07-19T00:00:00Z","timestamp":1784419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"LIBON Inc.","award":["GCU-202504870001"],"award-info":[{"award-number":["GCU-202504870001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rosacea is a chronic inflammatory skin disorder driven by dysregulated cathelicidin processing and excessive LL-37, which triggers a circuit involving Toll-like receptor 2 (TLR2)\/kallikrein-5 (KLK5)-dependent amplification and downstream mechanistic target of rapamycin complex 1 (mTORC1), NF-\u03baB, and NLR family pyrin domain containing 3 (NLRP3) inflammasome pathways. We hypothesized that poly-D,L-lactic acid (PDLLA) could attenuate this inflammatory cascade by inducing macrophage-derived interleukin (IL)-10. PDLLA increased IL-10 secretion from THP-1-derived macrophages in a dose-dependent manner. In LL-37-stimulated HaCaT keratinocytes, LL-37 decreased phosphorylated signal transducer and activator of transcription (pSTAT3)\/STAT3, DNA damage-inducible transcript 4 (DDIT4), and phosphorylated AMP-activated protein kinase (pAMPK)\/AMPK while increasing phosphorylated protein kinase B (pAKT)\/AKT and mTORC1 activation; conditioned media from PDLLA-treated macrophages (CMPDLLA) restored pSTAT3\/STAT3, DDIT4, and pAMPK\/AMPK, reduced pAKT\/AKT, and suppressed pmTOR\/mTOR. CMPDLLA attenuated downstream inflammatory responses, including NF-\u03baB nuclear translocation, VEGF production, and NLRP3-inflammasome-mediated IL-18 secretion. These findings were validated using an intradermal LL-37-injected mouse model. Compared with the normal control\/saline group, LL-37\/saline decreased IL-10, pSTAT3\/STAT3, DDIT4, and pAMPK\/AMPK while increasing pAKT\/AKT, pmTOR\/mTOR, pS6K\/S6K, TLR2\/KLK5\/LL-37, NF-\u03baB, VEGF, and NLRP3 inflammasome\/IL-18 signaling; PDLLA partially restored the STAT3\/DDIT4\u2013AMPK regulatory pattern and suppressed these disease-associated signals. Consequently, PDLLA treatment led to a pronounced reduction in clinical lesion area. Overall, PDLLA may attenuate LL-37-driven cutaneous inflammation by promoting an IL-10-linked STAT3\/DDIT4\u2013AKT\/AMPK program that suppresses mTORC1 and disrupts cathelicidin amplification, supporting its potential as an injectable immunomodulatory approach for rosacea-like skin inflammation.<\/jats:p>","DOI":"10.3390\/ijms27146425","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6425","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immunomodulatory Effects of Poly-D,L-Lactic Acid on LL-37-Driven Rosacea-like Inflammation via Suppression of mTORC1 Signaling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7486-9137","authenticated-orcid":false,"given":"Kyung-A","family":"Byun","sequence":"first","affiliation":[{"name":"Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea"},{"name":"LIBON Inc., Incheon 22006, Republic of Korea"},{"name":"Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Je-Young","family":"Park","sequence":"additional","affiliation":[{"name":"Oracle Dermatology Clinic, Seoul 06097, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyeon","family":"Oh","sequence":"additional","affiliation":[{"name":"LIBON Inc., Incheon 22006, Republic of Korea"},{"name":"Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4859-4069","authenticated-orcid":false,"given":"Ji Yeoun","family":"Shin","sequence":"additional","affiliation":[{"name":"Hev Dermatology Clinic, Seoul 06035, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suk Bae","family":"Seo","sequence":"additional","affiliation":[{"name":"SeoAh Song Dermatologic Clinic, Seoul 05557, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0595-5645","authenticated-orcid":false,"given":"Kuk Hui","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8678-8932","authenticated-orcid":false,"given":"Kyunghee","family":"Byun","sequence":"additional","affiliation":[{"name":"Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Republic of Korea"},{"name":"Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea"},{"name":"Department of Health Sciences and Technology, Gachon Advanced Institute for Health & Sciences and Technology (GAIHST), Gachon University, Incheon 21999, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/jidsymp.2011.2","article-title":"Epidermal proteases in the pathogenesis of rosacea","volume":"15","year":"2011","journal-title":"J. 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