{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:07:04Z","timestamp":1790104024202,"version":"4.0.1"},"reference-count":29,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,18]],"date-time":"2023-02-18T00:00:00Z","timestamp":1676678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Oklahoma Medical Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Activation of the Stimulator of Interferon Genes (STING) protein has paradoxical outcomes in skin disease. STING activation exacerbates psoriatic skin disease and delays wound healing in diabetic mice, yet it also facilitates wound healing in normal mice. To address the role of localized STING activation in the skin, mice were injected subcutaneously with a STING agonist, diamidobenzimidazole STING Agonist-1 (diAbZi). The effect of a prior inflammatory stimulus on STING activation was addressed by pre-treating mice intraperitoneally with poly (I:C). The skin at the injection site was evaluated for local inflammation, histopathology, immune cell infiltration, and gene expression. Serum cytokine levels were measured to assess systemic inflammatory responses. Localized diABZI injection induced severe skin inflammation with erythema, scaling, and induration. However, the lesions were self-limiting and resolved within 6 weeks. At the peak of inflammation, the skin showed epidermal thickening, hyperkeratosis, and dermal fibrosis. Neutrophils, CD3 T cells, and F4\/80 macrophages were present in the dermis and subcutaneous layers. Gene expression was consistent with increased local interferon and cytokine signaling. Interestingly, the poly (I:C)-pre-treated mice showed higher serum cytokine responses and developed worse inflammation with delayed wound resolution. Our study demonstrates that prior systemic inflammation amplifies STING-mediated inflammatory responses and skin disease.<\/jats:p>","DOI":"10.3390\/ijms24044128","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T04:28:57Z","timestamp":1676867337000},"page":"4128","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["STING Agonist-Induced Skin Inflammation Is Exacerbated with Prior Systemic Innate Immune Activation"],"prefix":"10.3390","volume":"24","author":[{"given":"Marcelina","family":"Pyclik","sequence":"first","affiliation":[{"name":"Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7301-5324","authenticated-orcid":false,"given":"Justyna","family":"Durslewicz","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna A.","family":"Papinska","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"},{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umesh S.","family":"Deshmukh","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"},{"name":"Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harini","family":"Bagavant","sequence":"additional","affiliation":[{"name":"Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/s41577-021-00524-z","article-title":"The cGAS\u2013STING Pathway as a Therapeutic Target in Inflammatory Diseases","volume":"21","author":"Decout","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1056\/NEJMoa1312625","article-title":"Activated STING in a Vascular and Pulmonary Syndrome","volume":"371","author":"Liu","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7941","DOI":"10.1073\/pnas.1818281116","article-title":"Hierarchy of clinical manifestations in SAVI N153S and V154M mouse models","volume":"116","author":"Motwani","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1111\/bph.15673","article-title":"The STING antagonist H-151 ameliorates psoriasis via suppression of STING\/NF-\u03baB-mediated inflammation","volume":"178","author":"Pan","year":"2021","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.jid.2021.08.430","article-title":"Cytosolic DNA\u2013Mediated STING-Dependent Inflammation Contributes to the Progression of Psoriasis","volume":"142","author":"Yu","year":"2022","journal-title":"J. Investig. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.bbrc.2022.04.085","article-title":"STING activation promotes inflammatory response and delays skin wound healing in diabetic mice","volume":"611","author":"Feng","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.jdermsci.2019.11.008","article-title":"Activation of STING signaling accelerates skin wound healing","volume":"97","author":"Mizutani","year":"2020","journal-title":"J. Dermatol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/s41586-018-0705-y","article-title":"Design of amidobenzimidazole STING receptor agonists with systemic activity","volume":"564","author":"Ramanjulu","year":"2018","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105015","DOI":"10.1016\/j.antiviral.2021.105015","article-title":"Inhibition of coronavirus infection by a synthetic STING agonist in primary human airway system","volume":"187","author":"Zhu","year":"2021","journal-title":"Antivir. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e00490-21","DOI":"10.1128\/JVI.00490-21","article-title":"Activation of STING Signaling Pathway Effectively Blocks Human Coronavirus Infection","volume":"95","author":"Liu","year":"2021","journal-title":"J. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eabi9002","DOI":"10.1126\/sciimmunol.abi9002","article-title":"A diamidobenzimidazole STING agonist protects against SARS-CoV-2 infection","volume":"6","author":"Humphries","year":"2021","journal-title":"Sci. Imunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"eabi9007","DOI":"10.1126\/sciimmunol.abi9007","article-title":"Pharmcological activation of STING blocks SARS-CoV-2 infection","volume":"6","author":"Li","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Garcia-Valtanen, P., Guzman-Genuino, R.M., Hayball, J.D., and Diener, K.R. (2020). Polyinosinic: Polycytidylic Acid and Murine Cytomegalovirus Modulate Expression of Murine IL-10 and IL-21 in White Adipose Tissue. Viruses, 12.","DOI":"10.3390\/v12050569"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"758","DOI":"10.3389\/fonc.2020.00758","article-title":"Pharmacological STING Activation Is a Potential Alternative to Overcome Drug-Resistance in Melanoma","volume":"14","author":"Chipurupalli","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/s41419-022-04664-5","article-title":"STING agonist diABZI induces PANoptosis and DNA mediated acute respiratory distress syndrome (ARDS)","volume":"13","author":"Culerier","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40001-017-0299-0","article-title":"Chemokine ligand-receptor interactions critically regulate cutaneous wound healing","volume":"23","author":"Hoff","year":"2018","journal-title":"Eur. J. Med. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1146\/annurev.iy.07.040189.000343","article-title":"Decay-Accelerating molecular biology and function","volume":"7","author":"Lublin","year":"1989","journal-title":"Ann. Rev. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.4049\/jimmunol.1402354","article-title":"Complement Deficiency Promotes Cutaneous Wound Healing in Mice","volume":"194","author":"Rafail","year":"2015","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"698522","DOI":"10.3389\/fimmu.2021.698522","article-title":"Thymic Stromal Lymphopoietin in Cutaneous Immune-Mediated Diseases","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.jid.2015.11.008","article-title":"TSLP Is a Potential Initiator of Collagen Synthesis and an Activator of CXCR4\/SDF-1 Axis in Keloid Pathogenesis","volume":"136","author":"Shin","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.stemcr.2022.01.017","article-title":"Thymic stromal lymphopoietin controls hair growth","volume":"17","author":"Shannon","year":"2022","journal-title":"Stem Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.jaci.2020.04.034","article-title":"Animal models of psoriasis\u2014Highlights and drawbacks","volume":"147","author":"Manzke","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5836","DOI":"10.4049\/jimmunol.0802999","article-title":"Imiquimod-Induced Psoriasis-Like Skin Inflammation in Mice Is Mediated via the IL-23\/IL-17 Axis 1","volume":"182","author":"Mourits","year":"2009","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Jabeen, M., Boisgard, A.S., Danoy, A., El Kholti, N., Salvi, J.P., Boulieu, R., Fromy, B., Verrier, B., and Lamrayah, M. (2020). Advanced characterization of imiquimod-induced psoriasis-like mouse model. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12090789"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Motedayen Aval, L., Pease, J.E., Sharma, R., and Pinato, D.J. (2020). Challenges and Opportunities in the Clinical Development of STING Agonists for Cancer Immunotherapy. J. Clin. Med., 9.","DOI":"10.3390\/jcm9103323"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s40425-019-0568-2","article-title":"Immunotherapeutic effects of intratumoral nanoplexed poly I:C","volume":"7","author":"Aznar","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_27","first-page":"1030","article-title":"Phenotypic changes of lymphocyte populations in psoriasiform dermatitis animal model","volume":"17","author":"Surcel","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.1084\/jem.20101048","article-title":"Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9","volume":"207","author":"Guiducci","year":"2010","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100153","DOI":"10.1016\/j.jtauto.2022.100153","article-title":"Systemic immune response to vimentin and granuloma formation in a model of pulmonary sarcoidosis","volume":"5","author":"Bagavant","year":"2022","journal-title":"J. Transl. Autoimmun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/4128\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:36:07Z","timestamp":1760121367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/4128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,18]]},"references-count":29,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24044128"],"URL":"https:\/\/doi.org\/10.3390\/ijms24044128","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,18]]}}}