{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T11:28:27Z","timestamp":1780572507791,"version":"3.54.1"},"reference-count":36,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"FUNDA\u00c7\u00c3O DE AMPARO \u00c0 PESQUISA DO ESTADO DE S\u00c3O PAULO (FAPESP)","doi-asserted-by":"publisher","award":["2019\/19949-7"],"award-info":[{"award-number":["2019\/19949-7"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Chronic, non-resolving inflammation is a major contributor to impaired wound healing in diabetes. Annexin A1 (AnxA1), a pro-resolving mediator, and its mimetic peptide Ac2\u201326 have demonstrated therapeutic potential in modulating inflammatory responses. In this study, we evaluated the effects of topical Ac2\u201326 hydrogel in a streptozotocin-induced diabetic wound model. Treatment significantly accelerated wound closure, improved tissue architecture, and reduced leukocyte infiltration. Immunohistochemical analysis revealed diminished mast cell accumulation and IL-1\u03b2 expression in treated wounds. Complementary transcriptomic profiling supported the downregulation of pro-inflammatory genes, including Il1b and mast cell-related mediators, confirming the peptide\u2019s regulatory effect on the wound immune landscape. Mounting evidence suggests that dysregulated mast cell activity plays a role in the heightened inflammatory tone and delayed tissue repair observed in diabetic wounds. In our model, Ac2\u201326 hydrogel treatment attenuated IL-1\u03b2 expression, suggesting an indirect downregulation of NLRP3 inflammasome activation, potentially mediated through mast cell modulation, though effects on other cell types within the wound microenvironment cannot be excluded. While definitive causality cannot be assigned, the integration of histological and transcriptomic data highlights mast cells as contributors to the IL-1\u03b2-driven inflammatory burden in diabetic wounds. These findings underscore the immunomodulatory capacity of Ac2\u201326 and its potential to restore resolution pathways in chronic wound settings, positioning it as a promising candidate for future therapeutic development.<\/jats:p>","DOI":"10.3390\/cells14130999","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T09:08:44Z","timestamp":1751447324000},"page":"999","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Ac2\u201326 Hydrogel Modulates IL-1\u03b2-Driven Inflammation via Mast Cell-Associated and Immune Regulatory Pathways in Diabetic Wounds"],"prefix":"10.3390","volume":"14","author":[{"given":"Monielle","family":"Sant\u2019Ana","sequence":"first","affiliation":[{"name":"Structural and Functional Biology Graduated Program, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 09913-030, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Andr\u00e9","family":"da Silva","sequence":"additional","affiliation":[{"name":"Department of Biology, School of Biosciences, Humanities and Exact Sciences, S\u00e3o Paulo State University (UNESP), S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5571-5722","authenticated-orcid":false,"given":"Luiz Philipe S.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Structural and Functional Biology Graduated Program, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 09913-030, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6979-4126","authenticated-orcid":false,"given":"Cristiane D.","family":"Gil","sequence":"additional","affiliation":[{"name":"Structural and Functional Biology Graduated Program, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 09913-030, SP, Brazil"},{"name":"Department of Biology, School of Biosciences, Humanities and Exact Sciences, S\u00e3o Paulo State University (UNESP), S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6293-4157","authenticated-orcid":false,"given":"Fernando L.","family":"Primo","sequence":"additional","affiliation":[{"name":"Department of Engineering of Bioprocess and Biotechnology, School of Pharmaceutical Sciences, S\u00e3o Paulo State University (UNESP), Araraquara 14800-903, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8760-8945","authenticated-orcid":false,"given":"Ana Paula","family":"Girol","sequence":"additional","affiliation":[{"name":"Structural and Functional Biology Graduated Program, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 09913-030, SP, Brazil"},{"name":"Experimental and Clinical Research Center (CEPEC), Padre Albino University Center (UNIFIPA), Catanduva 15809-144, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-7650","authenticated-orcid":false,"given":"Karin V.","family":"Greco","sequence":"additional","affiliation":[{"name":"Structural and Functional Biology Graduated Program, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 09913-030, SP, Brazil"},{"name":"Department of Surgical Biotechnology, Division of Surgery & Interventional Science, Royal Free Hospital, School of Medicine University College London (UCL), London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0918-2130","authenticated-orcid":false,"given":"Sonia M.","family":"Oliani","sequence":"additional","affiliation":[{"name":"Structural and Functional Biology Graduated Program, Federal University of S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 09913-030, SP, Brazil"},{"name":"Department of Biology, School of Biosciences, Humanities and Exact Sciences, S\u00e3o Paulo State University (UNESP), S\u00e3o Jos\u00e9 do Rio Preto 15054-000, SP, Brazil"},{"name":"Advanced Research Center in Medicine (CEPAM), Uni\u00e3o das Faculdades dos Grandes Lagos (Unilago), S\u00e3o Jos\u00e9 do Rio Preto 15030-070, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1089\/pho.2018.4453","article-title":"Effects of Photobiomodulation on Degranulation and Number of Mast Cells and Wound Strength in Skin Wound Healing of Streptozotocin-Induced Diabetic Rats","volume":"36","author":"Bagheri","year":"2018","journal-title":"Photomed. Laser Surg."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1016\/j.jid.2019.08.449","article-title":"Topical Application of a Mast Cell Stabilizer Improves Impaired Diabetic Wound Healing","volume":"40","author":"Tellechea","year":"2020","journal-title":"J. Investig. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Oliveira, M.P., Prates, J., Gimenes, A.D., Correa, S.G., and Oliani, S.M. (2021). Annexin A1 Mimetic Peptide Ac2\u201326 Modulates the Function of Murine Colonic and Human Mast Cells. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.689484"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Masini, M., Suleiman, M., Novelli, M., Marselli, L., Marchetti, P., and De Tata, V. (2021). Mast cells and the pancreas in human type 1 and type 2 diabetes. Cells, 10.","DOI":"10.3390\/cells10081875"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.1002\/eji.201545498","article-title":"Mast cells control insulitis and increase Treg cells to confer protection against STZ-induced type 1 diabetes in mice","volume":"45","author":"Carlos","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.2337\/db15-0340","article-title":"Mast cells regulate wound healing in diabetes","volume":"65","author":"Tellechea","year":"2016","journal-title":"Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1177\/1534734613476519","article-title":"Update on the diabetic foot 2012: The 14th biennial Malvern Diabetic Foot Conference, May 9\u201311, 2012","volume":"12","author":"Lamont","year":"2013","journal-title":"Int. J. Low. Extrem. Wounds"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.avsg.2015.11.025","article-title":"Burden of infected diabetic foot ulcers on hospital admissions and costs","volume":"33","author":"Hicks","year":"2016","journal-title":"Ann. Vasc. Surg."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1084\/jem.20082179","article-title":"Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria","volume":"206","author":"Nakamura","year":"2009","journal-title":"J. Exp. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.immuni.2012.04.013","article-title":"Critical Role for Mast Cells in Interleukin-1\u03b2-Driven Skin Inflammation Associated with an Activating Mutation in the Nlrp3 Protein","volume":"37","author":"Nakamura","year":"2012","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.tibs.2016.09.002","article-title":"Mechanism and Regulation of NLRP3 Inflammasome Activation","volume":"41","author":"He","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/nature10759","article-title":"Inflammasomes in health and disease","volume":"481","author":"Strowig","year":"2012","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1111\/imr.12285","article-title":"NLRP3 at the interface of metabolism and inflammation","volume":"265","author":"Haneklaus","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/imm.13184","article-title":"The role of annexin A1 in the modulation of the NLRP3 inflammasome","volume":"160","author":"Vago","year":"2020","journal-title":"Immunology"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Sanches, J.M., Correia-Silva, R.D., Duarte, G.H.B., Fernandes, A.M.A.P., S\u00e1nchez-Vinces, S., Carvalho, P.O., Oliani, S.M., Bortoluci, K.R., Moreira, V., and Gil, C.D. (2021). Role of annexin A1 in NLRP3 inflammasome activation in murine neutrophils. Cells, 10.","DOI":"10.3390\/cells10010121"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Ma, Q., Velagapudi, R., Barclay, W.E., Rodriguiz, R.M., Wetsel, W.C., Yang, T., Shinohara, M.L., and Terrando, N. (2022). Annexin-A1 Tripeptide Attenuates Surgery-Induced Neuroinflammation and Memory Deficits Through Regulation the NLRP3 Inflammasome. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.856254"},{"key":"ref_17","first-page":"60","article-title":"Annexin 1: An endogenous anti-inflammatory protein","volume":"18","author":"Perretti","year":"2003","journal-title":"News Physiol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mimura, K.K.O., Moraes, A.R., Miranda, A.C., Greco, R., Ansari, T., Sibbons, P., Greco, K.V., and Oliani, S.M. (2016). Mechanisms underlying heterologous skin scaffold mediated tissue remodeling. Sci. Rep., 6.","DOI":"10.1038\/srep35074"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.micpath.2018.03.050","article-title":"Mast cell heterogeneity and anti-inflammatory annexin a1 expression in lepreosy skin lesions","volume":"118","author":"Costa","year":"2018","journal-title":"Microb. Pathog."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lacerda, J.Z., Drewes, C.C., Mimura, K.K.O., Zanon, C.d.F., Ansari, T., Gil, C.D., Greco, K.V., Farsky, S.H.P., and Oliani, S.M. (2018). Annexin A12\u201326 treatment improves skin heterologous transplantation by modulating inflammation and angiogenesis processes. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.01015"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Parisi, J.S., Corr\u00eaa, M.C., and Gil, C.D. (2019). Lack of Endogenous Annexin A1 Increases Mast Cell Activation and Exacerbates Experimental Atopic Dermatitis. Cells, 8.","DOI":"10.3390\/cells8010051"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.cjtee.2020.02.002","article-title":"Annexin A1 involved in the regulation of inflammation and cell signaling pathways","volume":"23","author":"Han","year":"2020","journal-title":"Chin. J. Traumatol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Girol, A.P., Zanon, C.d.F., Caruso, \u00cd.P., Costa, S.d.S., Souza, H.R., Corn\u00e9lio, M.L., and Oliani, S.M. (2021). Anti-Inflammatory Profiles in Endotoxin-Induced Uveitis. Cells, 10.","DOI":"10.3390\/cells10113170"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Souza, H.R., de Azevedo, L.R., Possebon, L., Costa, S.d.S., Iyomasa-Pilon, M.M., Oliani, S.M., Girol, A.P., and D\u2019ACquisto, F. (2017). Heterogeneity of mast cells and expression of Annexin A1 protein in a second degree burn model with silver sulfadiazine treatment. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0173417"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sant, M., Amantino, C.F., Silva, R.A., Gil, C.D., Greco, K.V., Primo, F.L., Girol, A.P., and Oliani, S.M. (2023). Annexin A12\u201326 hydrogel improves healing properties in an experimental skin lesion after induction of type 1 diabetes. Biomed. Pharmacother., 165.","DOI":"10.1016\/j.biopha.2023.115230"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.2337\/db11-0825","article-title":"\u03b11-Acid Glycoprotein decreases neutrophil migration and increases susceptibility to sepsis in diabetic mice","volume":"61","author":"Spiller","year":"2012","journal-title":"Diabetes"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Macleod, T., Berekmeri, A., Bridgewood, C., Stacey, M., and Mcgonagle, D. (2021). Wittmann M. The Immunological Impact of IL-1 Family Cytokines on the Epidermal Barrier. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.808012"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1124\/jpet.104.080473","article-title":"A novel effect for annexin 1-derived peptide ac2-26: Reduction of allergic inflammation in the rat","volume":"313","author":"Bonavita","year":"2005","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S1734-1140(10)70307-8","article-title":"Anti-allergic drugs and the Annexin-A1 system","volume":"62","author":"Yazid","year":"2011","journal-title":"Pharmacol. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yazid, S., Sinniah, A., Solito, E., Calder, V., Flower, R.J., and Ryffel, B. (2013). Anti-allergic cromones inhibit histamine and eicosanoid release from activated human and murine mast cells by releasing Annexin A1. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0058963"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Sinniah, A., Yazid, S., Bena, S., Oliani, S.M., Perretti, M., and Flower, R.J. (2019). Endogenous annexin-A1 negatively regulates mast cell-mediated allergic reactions. Front. Pharmacol., 10.","DOI":"10.3389\/fphar.2019.01313"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.diabres.2014.04.006","article-title":"Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes","volume":"105","author":"Esser","year":"2014","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4519","DOI":"10.1007\/s12325-020-01499-4","article-title":"Mast Cells in Diabetes and Diabetic Wound Healing","volume":"37","author":"Dong","year":"2020","journal-title":"Adv. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103981","DOI":"10.1016\/j.etap.2022.103981","article-title":"Annexin A1 inhibition facilitates NLRP3 inflammasome activation in arsenic-induced insulin resistance in rat liver","volume":"96","author":"Wu","year":"2022","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1038\/nrd.2018.97","article-title":"Targeting the NLRP3 inflammasome in inflammatory diseases","volume":"17","author":"Mangan","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_36","first-page":"9902","article-title":"ROS-activated NLRP3 inflammasome initiates inflammation in delayed wound healing in diabetic rats","volume":"10","author":"Dai","year":"2017","journal-title":"Int. J. Clin. Exp. Pathol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/13\/999\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:01:42Z","timestamp":1760032902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/13\/999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,30]]},"references-count":36,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["cells14130999"],"URL":"https:\/\/doi.org\/10.3390\/cells14130999","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,30]]}}}