{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:52:41Z","timestamp":1792788761563,"version":"4.5.0"},"reference-count":0,"publisher":"American Diabetes Association","license":[{"start":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T00:00:00Z","timestamp":1792022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"name":"National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases","award":["1F31DK136228-01A1"],"award-info":[{"award-number":["1F31DK136228-01A1"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases","award":["1R01DK136815-01"],"award-info":[{"award-number":["1R01DK136815-01"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing pancreatic \u03b2-cells. We published that an IgG3 Toll-like receptor 4 (TLR4)\/myeloid differentiation factor 2 (MD2) agonistic antibody (TLR4-Ab) reversed acute T1D in NOD mice by induction of myeloid-derived suppressor cells (MDSCs), but the mechanism of MDSC induction was unclear. Here we show that TLR4-Ab reversal of acute T1D induced profound intraislet immune and endocrine changes in single-cell RNA sequencing compared with controls. Islet-infiltrating S100A9+ cells significantly upregulated 18 genes associated with MDSCs, including Nos2, the gene responsible for inducible nitric oxide synthase (iNOS) production. TLR4-Ab treatment induced significant changes in \u03b2-cell gene expression, with markedly reduced endoplasmic reticulum stress and reduced unfolded protein response. Bone marrow (BM) cells cultured with TLR4-Ab, but not granulocyte macrophage\u2013colony-stimulating factor or lipopolysaccharide, induced MDSCs that suppressed T cells, and blockade of iNOS activity eliminated T-cell suppression. Blockade of interleukin 10 (IL-10) signaling during BM differentiation prevented T-cell suppression induced by TLR4-Ab\u2013MDSC, demonstrating a central role for IL-10 in TLR4-Ab\u2013mediated MDSC development. Reporter cell assays demonstrated predominant endosomal signaling with TLR4-Ab, and soluble (not plate-bound) TLR4-Ab was necessary for MDSC induction. TLR4-Ab treatment of T1D therefore induces an IL-10\u2013dependent immunoregulatory MDSC response, which significantly downregulates \u03b2-cell stress.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>Therapy with IgG3 Toll-like receptor 4 (TLR4)\/myeloid differentiation factor 2 (MD2) agonistic antibody (TLR4-Ab) is a novel approach to type 1 diabetes (T1D) immunotherapy that targets the innate immune system by inducing immunoregulatory myeloid-derived suppressor cells (MDSCs). We sought to define the mechanisms by which TLR4-Ab induces MDSCs and how they reverse T1D. TLR4-Ab induction of MDSCs requires interleukin 10 signaling in the bone marrow, and MDSCs mediate suppression via inducible nitric oxide synthase. Induction of immunoregulatory MDSCs results in profound downregulation of \u03b2-cell endoplasmic reticulum stress and unfolded protein response associated with acute T1D. Establishing mechanisms by which TLR4-Ab reverses acute T1D defines new therapeutic pathways for human T1D that target innate immunity to restore immune tolerance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db26-0636","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:45:49Z","timestamp":1792075549000},"update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":0,"title":["Reversal of T1D and Rapid Reduction of \u03b2-Cell Stress by IL-10\u2013Dependent MDSCs Induced by TLR4-Ab"],"prefix":"10.2337","author":[{"given":"Nicolle K.","family":"Martin","sequence":"first","affiliation":[{"name":"1Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA"},{"name":"2Graduate Group in Immunology, University of California, Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke S.","family":"Heuer","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ixchel M.","family":"Urbano","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA"},{"name":"2Graduate Group in Immunology, University of California, Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shana L.","family":"Cohen","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Rojas","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA"},{"name":"3Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogot\u00e1, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weici","family":"Zhang","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J.","family":"Bednar","sequence":"additional","affiliation":[{"name":"4Bioscience Immunology, AstraZeneca, Gaithersburg, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany P.","family":"Cummings","sequence":"additional","affiliation":[{"name":"5Department of Surgery, Center for Alimentary and Metabolic Sciences, School of Medicine, University of California, Davis, Sacramento, CA"},{"name":"6Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9569-3932","authenticated-orcid":false,"given":"William M.","family":"Ridgway","sequence":"additional","affiliation":[{"name":"1Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, Davis, CA"},{"name":"2Graduate Group in Immunology, University of California, Davis, Davis, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2026,10,15]]},"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db26-0636\/898922\/db260636.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/doi\/10.2337\/db26-0636\/898922\/db260636.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:45:49Z","timestamp":1792075549000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/doi\/10.2337\/db26-0636\/172813\/Reversal-of-T1D-and-Rapid-Reduction-of-Cell-Stress"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,15]]},"references-count":0,"URL":"https:\/\/doi.org\/10.2337\/db26-0636","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,15]]},"article-number":"db260636"}}