دورية أكاديمية
أعرض في EDS

Hypoxia inducible factor 2α promotes tolerogenic macrophage development during cardiac transplantation through transcriptional regulation of colony stimulating factor 1 receptor.

التفاصيل البيبلوغرافية
العنوان: Hypoxia inducible factor 2α promotes tolerogenic macrophage development during cardiac transplantation through transcriptional regulation of colony stimulating factor 1 receptor.
المؤلفون: DeBerge M; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.; Department of Anesthesiology, Critical Care and Pain Medicine, University of Texas Health Science Center, Houston, TX 77030., Schroth S; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611., Du F; Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208., Yeap XY; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611., Wang JJ; Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL 60611., Zhang ZJ; Department of Surgery, Comprehensive Transplant Center, Northwestern University, Chicago, IL 60611., Ansari MJ; Division of Nephrology and Hypertension, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611., Scott EA; Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208., Thorp EB; Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
المصدر: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jun 25; Vol. 121 (26), pp. e2319623121. Date of Electronic Publication: 2024 Jun 18.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : National Academy of Sciences
مواضيع طبية MeSH: Heart Transplantation* , Macrophages*/metabolism , Macrophages*/immunology , Basic Helix-Loop-Helix Transcription Factors*/metabolism , Basic Helix-Loop-Helix Transcription Factors*/genetics , Transplantation Tolerance*/immunology , Monocytes*/immunology , Monocytes*/metabolism, Animals ; Mice ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics ; Graft Rejection/immunology ; Graft Rejection/prevention & control ; Graft Rejection/genetics ; Mice, Inbred C57BL ; Gene Expression Regulation/drug effects ; Graft Survival/immunology ; Graft Survival/drug effects ; Male
مستخلص: Solid organ transplantation mobilizes myeloid cells, including monocytes and macrophages, which are central protagonists of allograft rejection. However, myeloid cells can also be functionally reprogrammed by perioperative costimulatory blockade to promote a state of transplantation tolerance. Transplantation tolerance holds promise to reduce complications from chronic immunosuppression and promote long-term survival in transplant recipients. We sought to identify different mediators of transplantation tolerance by performing single-cell RNA sequencing of acute rejecting or tolerized cardiac allografts. This led to the unbiased identification of the transcription factor, hypoxia inducible factor (HIF)-2α, in a subset of tolerogenic monocytes. Using flow cytometric analyses and mice with conditional loss or gain of function, we uncovered that myeloid cell expression of HIF-2α was required for costimulatory blockade-induced transplantation tolerance. While HIF-2α was dispensable for mobilization of tolerogenic monocytes, which were sourced in part from the spleen, it promoted the expression of colony stimulating factor 1 receptor (CSF1R). CSF1R mediates monocyte differentiation into tolerogenic macrophages and was found to be a direct transcriptional target of HIF-2α in splenic monocytes. Administration of the HIF stabilizer, roxadustat, within micelles to target myeloid cells, increased HIF-2α in splenic monocytes, which was associated with increased CSF1R expression and enhanced cardiac allograft survival. These data support further exploration of HIF-2α activation in myeloid cells as a therapeutic strategy for transplantation tolerance.
Competing Interests: Competing interests statement:The authors declare no competing interest.
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معلومات مُعتمدة: R01 HL139812 United States HL NHLBI NIH HHS
فهرسة مساهمة: Keywords: macrophage; tolerance; transplant
المشرفين على المادة: 1B37H0967P (endothelial PAS domain-containing protein 1)
0 (Basic Helix-Loop-Helix Transcription Factors)
0 (Receptors, Granulocyte-Macrophage Colony-Stimulating Factor)
تواريخ الأحداث: Date Created: 20240618 Date Completed: 20240618 Latest Revision: 20240701
رمز التحديث: 20240701
مُعرف محوري في PubMed: PMC11214057
DOI: 10.1073/pnas.2319623121
PMID: 38889142
قاعدة البيانات: MEDLINE
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.2319623121