Endosomal Sequestration of TLR4 Antibody Induces Myeloid-Derived Suppressor Cells and Reverses Acute Type 1 Diabetes
| Autor: | Kathryn C.S. Locker, Kritika Kachapati, Yuehong Wu, Kyle J. Bednar, David Adams, Caroline Patel, Hiroki Tsukamoto, Luke S. Heuer, Bruce J. Aronow, Andrew B. Herr, William M. Ridgway |
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| Rok vydání: | 2022 |
| Předmět: |
CD11b Antigen
Myeloid-Derived Suppressor Cells Endocrinology Diabetes and Metabolism Antibodies Monoclonal Bone Marrow Cells Endosomes Toll-Like Receptor 4 Mice Diabetes Mellitus Type 1 Gene Expression Regulation Mice Inbred NOD Internal Medicine Animals Female lipids (amino acids peptides and proteins) Immunology and Transplantation |
| Zdroj: | Diabetes |
| ISSN: | 0012-1797 |
| DOI: | 10.2337/db21-0426 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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