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Recently, Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)\u2010positive macrophages have been shown to play important roles in regulating tissue inflammation and repair. However, it remains unclear whether they can mitigate the transition from acute kidney injury to chronic kidney disease (the AKI\u2013CKD transition).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The AKI\u2013CKD transition was generated by unilateral ischaemia\u2013reperfusion injury (UIRI) in wild\u2010type (WT) and Trem2 knockout mice. F4\/80 magnetic beads were used to isolate renal macrophages. Flow cytometry was used to determine the levels of TREM2 and CD11b levels. Quantitative reverse transcription polymerase chain reaction (qRT\u2010PCR), Western blotting and histological staining were performed to determine the expression of cytokines and fibrotic markers. RNA\u2010seq was used to investigate transcriptomic changes between WT and Trem2 knockout bone marrow\u2010derived macrophages (BMDMs). TREM2\u2010overexpressing macrophages were generated using lentivirus and transferred intravenously to UIRI mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TREM2 macrophages exhibited a strong renal protective effect on the AKI\u2013CKD transition. Genetic deletion of Trem2 resulted in increased renal inflammation and exacerbated renal injury and fibrosis in UIRI mice. Interestingly, we found that hypoxia could increase TREM2 expression in macrophages via HIF\u20101\u03b1. Upregulated TREM2 expression enhanced macrophage phagocytosis and suppressed the expression of pro\u2010inflammatory cytokines, resulting in lower levels of apoptosis and fibrosis in tubular epithelial cells. Using RNA\u2010seq analysis, we showed that the regulatory effects of TREM2 were orchestrated by the PI3K\u2010AKT pathway. Pharmacological regulation of the PI3K\u2010AKT pathway could modulate the macrophage\u2010mediated inflammation and phagocytosis. In addition, an adoptive cell therapy using TREM2\u2010overexpressing macrophages effectively reduced the immune cell infiltration, renal injury and fibrosis in UIRI mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study not only provides valuable mechanistic insights into the role of Trem2 in the AKI\u2013CKD transition but also offers a new avenue for TREM2\u2010overexpressing macrophage\u2010based adoptive cell therapy to treat kidney diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>TREM2 knockout worsens kidney injury and accelerates AKI\u2013CKD transition.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>TREM2 is upregulated by hypoxia via HIF1\u03b1 in AKI\u2013CKD transition.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>An adoptive cell therapy using TREM2\u2010overexpressing macrophages reduces kidney inflammation and fibrosis.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70252","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T09:16:17Z","timestamp":1741684577000},"source":"Crossref","is-referenced-by-count":16,"title":["An adoptive cell therapy with TREM2\u2010overexpressing macrophages mitigates the transition from acute kidney injury to chronic kidney 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Memorial Hospital Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong\u2010Hong Kong Joint Laboratory for RNA Medicine, Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanzhi","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chipeng","family":"Guo","sequence":"additional","affiliation":[{"name":"Basic and Translational Medical Research Center, Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University  Guangzhou Guangdong China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong\u2010Hong Kong Joint Laboratory for RNA 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