PMID- 36611129 OWN - NLM STAT- MEDLINE DCOM- 20230321 LR - 20230321 IS - 1437-7799 (Electronic) IS - 1342-1751 (Linking) VI - 27 IP - 4 DP - 2023 Apr TI - HLA class II antibody activation of endothelial cells induces M2 macrophage differentiation in peripheral blood. PG - 309-320 LID - 10.1007/s10157-022-02307-9 [doi] AB - BACKGROUND: Donor-specific human leukocyte antigen (HLA) class II antibodies (HLA-II Abs) combined with allogeneic endothelial cells (ECs) mediate high-risk rejection in kidney transplant patients. Macrophage accumulation is a significant histological feature of antibody-mediated rejection (AMR) in kidney transplant patients. Here, we further investigated the effect of HLA-II Abs on macrophage phenotypes to provide theoretical basis for clinical treatment of AMR. METHODS: We prepared an experimental model containing HLA-II Ab-stimulated microvascular ECs and peripheral blood mononuclear cells (PBMCs) co-culture and explored the potential relationship of HLA-II Ab, ECs activation, and macrophage differentiation. Immune phenotype of macrophage subsets was analyzed and quantified by flow cytometry. HLA-II Ab activation of ECs induces M2 macrophage differentiation signal pathways which were investigated by qPCR and western blotting. RESULTS: The stimulation of ECs by F(ab')(2) fragment of HLA-II Abs led to phosphorylation of PI3K, Akt, and mTOR, which mediated IL-10, ICAM-1, VCAM-1 secretion. The enhanced ICAM-1 and IL-10 promoted the migration of PBMCs and their differentiation into CD68(+) and CD163(+) (M2-type) macrophages, respectively, but not CD86(+) macrophages. CONCLUSION: These findings revealed the PI3K/Akt/mTOR signal pathways activated by HLA-II Abs in ECs and the immune regulation ability of HLA-II Abs to induce PBMC differentiation. CI - (c) 2022. The Author(s), under exclusive licence to The Japanese Society of Nephrology. FAU - Guo, Yingcong AU - Guo Y AD - Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China. FAU - Zheng, Bingxuan AU - Zheng B AD - Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China. FAU - Tian, Puxun AU - Tian P AD - Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China. AD - Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Zheng, Jin AU - Zheng J AD - Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China. AD - Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Li, Yang AU - Li Y AD - Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China. AD - Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Ding, Xiaoming AU - Ding X AD - Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China. AD - Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Xue, Wujun AU - Xue W AD - Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China. AD - Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China. FAU - Ding, Chenguang AU - Ding C AD - Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 West Yanta Road, Xi'an, 710061, China. doctor_ding@xjtu.edu.cn. AD - Institute of Organ Transplantation, Xi'an Jiaotong University, Xi'an, 710061, China. doctor_ding@xjtu.edu.cn. LA - eng GR - 82070768/National Natural Science Foundation of China (NSFC)/ GR - 2021KW-53/Key Research and Development Program of Shaanxi Province/ GR - xjj2018091/Fundamental Research Funds for the Central Universities/ GR - XJTU1AF-CRF-2019-008/Clinical Research Award of the First Affiliated Hospital of Xi'an Jiaotong University/ GR - 2019JYJH04/Special Supportive Program for Organ Transplantation by COTDF/ PT - Journal Article DEP - 20230107 PL - Japan TA - Clin Exp Nephrol JT - Clinical and experimental nephrology JID - 9709923 RN - 130068-27-8 (Interleukin-10) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - 0 (HLA Antigens) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Humans MH - *Endothelial Cells/metabolism MH - *Leukocytes, Mononuclear MH - Interleukin-10/metabolism/pharmacology MH - Intercellular Adhesion Molecule-1/metabolism/pharmacology MH - Proto-Oncogene Proteins c-akt/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism/pharmacology MH - HLA Antigens MH - TOR Serine-Threonine Kinases/metabolism/pharmacology MH - Macrophages MH - Cell Differentiation MH - Graft Rejection OTO - NOTNLM OT - Antibody-mediated rejection OT - Endothelial cells OT - HLA-II Abs OT - M2 macrophage OT - PBMCs EDAT- 2023/01/08 06:00 MHDA- 2023/03/22 06:00 CRDT- 2023/01/07 23:20 PHST- 2022/04/01 00:00 [received] PHST- 2022/11/30 00:00 [accepted] PHST- 2023/01/08 06:00 [pubmed] PHST- 2023/03/22 06:00 [medline] PHST- 2023/01/07 23:20 [entrez] AID - 10.1007/s10157-022-02307-9 [pii] AID - 10.1007/s10157-022-02307-9 [doi] PST - ppublish SO - Clin Exp Nephrol. 2023 Apr;27(4):309-320. doi: 10.1007/s10157-022-02307-9. Epub 2023 Jan 7.