{"doi":"10.2337/db21-0426","title":"Endosomal Sequestration of TLR4 Antibody Induces Myeloid-Derived Suppressor Cells and Reverses Acute Type 1 Diabetes","abstract":"We previously showed that treating NOD mice with an agonistic monoclonal anti-TLR4/MD2 antibody (TLR4-Ab) reversed acute type 1 diabetes (T1D). Here, we show that TLR4-Ab reverses T1D by induction of myeloid-derived suppressor cells (MDSCs). Unbiased gene expression analysis after TLR4-Ab treatment demonstrated upregulation of genes associated with CD11b+Ly6G+ myeloid cells and downregulation of T-cell genes. Further RNA sequencing of purified, TLR4-Ab-treated CD11b+ cells showed significant upregulation of genes associated with bone marrow-derived CD11b+ cells and innate immune system genes. TLR4-Ab significantly increased percentages and numbers of CD11b+ cells. TLR4-Ab-induced CD11b+ cells, derived ex vivo from TLR4-Ab-treated mice, suppress T cells, and TLR4-Ab-conditioned bone marrow cells suppress acute T1D when transferred into acutely diabetic mice. Thus, the TLR4-Ab-induced CD11b+ cells, by the currently accepted definition, are MDSCs able to reverse T1D. To understand the TLR4-Ab mechanism, we compared TLR4-Ab with TLR4 agonist lipopolysaccharide (LPS), which cannot reverse T1D. TLR4-Ab remains sequestered at least 48 times longer than LPS within early endosomes, alters TLR4 signaling, and downregulates inflammatory genes and proteins, including nuclear factor-κB. TLR4-Ab in the endosome, therefore, induces a sustained, attenuated inflammatory response, providing an ideal \"second signal\" for the activation/maturation of MDSCs that can reverse acute T1D.","journal":"Diabetes","year":2022,"id":270559,"datarank":0.5719567878004188,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.17609818835812996,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.17609818835812996,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":9,"citers_with_citation_signal":9,"citers_with_endowment":9,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":true,"deposit_databanks":{"figshare":["10.2337/figshare.17185826"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":935327,"name":"Kritika Kachapati","orcid":null,"position":1,"is_corresponding":false},{"id":763455,"name":"Yuehong Wu","orcid":"0000-0003-3590-2090","position":2,"is_corresponding":false},{"id":935328,"name":"Kyle J. Bednar","orcid":null,"position":3,"is_corresponding":false},{"id":503099,"name":"David Adams","orcid":"0000-0001-6776-0336","position":4,"is_corresponding":false},{"id":934813,"name":"Caroline Patel","orcid":"0000-0002-8165-6014","position":5,"is_corresponding":false},{"id":934814,"name":"Hiroki Tsukamoto","orcid":"0000-0002-4585-1656","position":6,"is_corresponding":false},{"id":913236,"name":"Luke S. Heuer","orcid":"0009-0008-5539-2968","position":7,"is_corresponding":false},{"id":71644,"name":"Bruce J. Aronow","orcid":"0000-0001-5109-6514","position":8,"is_corresponding":false},{"id":329766,"name":"Andrew B. Herr","orcid":"0000-0002-3598-3399","position":9,"is_corresponding":false},{"id":378099,"name":"William M. Ridgway","orcid":"0000-0002-9569-3932","position":10,"is_corresponding":false},{"id":784879,"name":"Kathryn C. S. Locker","orcid":"0000-0002-3669-3617","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T00:27:31.019242Z","pmid":"35040474","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}