{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:10:13Z","timestamp":1791544213918,"version":"4.3.4"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T00:00:00Z","timestamp":1712880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cystic Fibrosis Foundation (CFF) Research","award":["VOYNOW19G0 (JAV)"],"award-info":[{"award-number":["VOYNOW19G0 (JAV)"]}]},{"name":"Cystic Fibrosis Foundation (CFF) Research","award":["R01 HL146811-01A1 (JAV)"],"award-info":[{"award-number":["R01 HL146811-01A1 (JAV)"]}]},{"name":"Cystic Fibrosis Foundation (CFF) Research","award":["PR180925 (JAV)"],"award-info":[{"award-number":["PR180925 (JAV)"]}]},{"name":"National Institutes of Health (NIH)","award":["VOYNOW19G0 (JAV)"],"award-info":[{"award-number":["VOYNOW19G0 (JAV)"]}]},{"name":"National Institutes of Health (NIH)","award":["R01 HL146811-01A1 (JAV)"],"award-info":[{"award-number":["R01 HL146811-01A1 (JAV)"]}]},{"name":"National Institutes of Health (NIH)","award":["PR180925 (JAV)"],"award-info":[{"award-number":["PR180925 (JAV)"]}]},{"name":"U.S. Department of Defense (DOD) Congressionally Directed Medical Research Programs (CDMRP) Peer Reviewed Medical Research Program (PRMRP)","award":["VOYNOW19G0 (JAV)"],"award-info":[{"award-number":["VOYNOW19G0 (JAV)"]}]},{"name":"U.S. Department of Defense (DOD) Congressionally Directed Medical Research Programs (CDMRP) Peer Reviewed Medical Research Program (PRMRP)","award":["R01 HL146811-01A1 (JAV)"],"award-info":[{"award-number":["R01 HL146811-01A1 (JAV)"]}]},{"name":"U.S. Department of Defense (DOD) Congressionally Directed Medical Research Programs (CDMRP) Peer Reviewed Medical Research Program (PRMRP)","award":["PR180925 (JAV)"],"award-info":[{"award-number":["PR180925 (JAV)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neutrophil elastase (NE) is taken up by macrophages, retains intracellular protease activity, and induces a pro-inflammatory phenotype. However, the mechanism of NE-induced pro-inflammatory polarization of macrophages is not well understood. We hypothesized that intracellular NE degrades histone deacetylases (HDAC) and Sirtuins, disrupting the balance of lysine acetylation and deacetylation and resulting in nuclear to cytoplasmic translocation of a major alarmin, High Mobility Group Box 1 (HMGB1), a pro-inflammatory response in macrophages. Human blood monocytes were obtained from healthy donors or from subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Monocytes were differentiated into blood monocyte derived macrophages (BMDMs) in vitro. Human BMDMs were exposed to NE or control vehicle, and the abundance of HDACs and Sirtuins was determined by Western blotting of total cell lysates or nuclear extracts or determined by ELISA. HDAC, Sirtuin, and Histone acetyltransferase (HAT) activities were measured. NE degraded most HDACs and Sirtuin (Sirt)1, resulting in decreased HDAC and sirtuin activities, with minimal change in HAT activity. We then evaluated whether the NE-induced loss of Sirt activity or loss of HDAC activities would alter the cellular localization of HMGB1. NE treatment or treatment with Trichostatin A (TSA), a global HDAC inhibitor, both increased HMGB1 translocation from the nucleus to the cytoplasm, consistent with HMGB1 activation. NE significantly degraded Class I and II HDAC family members and Sirt 1, which shifted BMDMs to a pro-inflammatory phenotype.<\/jats:p>","DOI":"10.3390\/ijms25084265","type":"journal-article","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T03:34:37Z","timestamp":1712892877000},"page":"4265","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neutrophil Elastase Degrades Histone Deacetylases and Sirtuin 1 in Primary Human Monocyte Derived Macrophages"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7347-3188","authenticated-orcid":false,"given":"Shuo","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Pediatric Pulmonary Medicine, Children\u2019s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gamze B.","family":"Bulut","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonary Medicine, Children\u2019s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apparao B.","family":"Kummarapurugu","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonary Medicine, Children\u2019s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonary Medicine, Children\u2019s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2437-2859","authenticated-orcid":false,"given":"Judith A.","family":"Voynow","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonary Medicine, Children\u2019s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Voynow, J.A., and Shinbashi, M. 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