{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:15:09Z","timestamp":1787202909575,"version":"build-2736575974"},"reference-count":56,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T00:00:00Z","timestamp":1703116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Netherlands Organization for Scientific Research NWO","award":["91712386"],"award-info":[{"award-number":["91712386"]}]},{"name":"Netherlands Organization for Scientific Research NWO","award":["13A3D301"],"award-info":[{"award-number":["13A3D301"]}]},{"name":"Netherlands Organization for Scientific Research NWO","award":["457002002"],"award-info":[{"award-number":["457002002"]}]},{"name":"Dutch Kidney Foundation","award":["91712386"],"award-info":[{"award-number":["91712386"]}]},{"name":"Dutch Kidney Foundation","award":["13A3D301"],"award-info":[{"award-number":["13A3D301"]}]},{"name":"Dutch Kidney Foundation","award":["457002002"],"award-info":[{"award-number":["457002002"]}]},{"name":"China Scholarship Council (CSC)","award":["91712386"],"award-info":[{"award-number":["91712386"]}]},{"name":"China Scholarship Council (CSC)","award":["13A3D301"],"award-info":[{"award-number":["13A3D301"]}]},{"name":"China Scholarship Council (CSC)","award":["457002002"],"award-info":[{"award-number":["457002002"]}]},{"DOI":"10.13039\/501100001826","name":"NWO-FAPESP","doi-asserted-by":"publisher","award":["91712386"],"award-info":[{"award-number":["91712386"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"NWO-FAPESP","doi-asserted-by":"publisher","award":["13A3D301"],"award-info":[{"award-number":["13A3D301"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"NWO-FAPESP","doi-asserted-by":"publisher","award":["457002002"],"award-info":[{"award-number":["457002002"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Chronic kidney disease often leads to kidney dysfunction due to renal fibrosis, regardless of the initial cause of kidney damage. Macrophages are crucial players in the progression of renal fibrosis as they stimulate inflammation, activate fibroblasts, and contribute to extracellular matrix deposition, influenced by their metabolic state. Nucleotide-binding domain and LRR-containing protein X (NLRX1) is an innate immune receptor independent of inflammasomes and is found in mitochondria, and it plays a role in immune responses and cell metabolism. The specific impact of NLRX1 on macrophages and its involvement in renal fibrosis is not fully understood. Methods: To explore the specific role of NLRX1 in macrophages, bone-marrow-derived macrophages (BMDMs) extracted from wild-type (WT) and NLRX1 knockout (KO) mice were stimulated with pro-inflammatory and pro-fibrotic factors to induce M1 and M2 polarization in vitro. The expression levels of macrophage polarization markers (Nos2, Mgl1, Arg1, and Mrc1), as well as the secretion of transforming growth factor \u03b2 (TGF\u03b2), were measured using RT-PCR and ELISA. Seahorse-based bioenergetics analysis was used to assess mitochondrial respiration in na\u00efve and polarized BMDMs obtained from WT and NLRX1 KO mice. In vivo, WT and NLRX1 KO mice were subjected to unilateral ureter obstruction (UUO) surgery to induce renal fibrosis. Kidney injury, macrophage phenotypic profile, and fibrosis markers were assessed using RT-PCR. Histological staining (PASD and Sirius red) was used to quantify kidney injury and fibrosis. Results: Compared to the WT group, an increased gene expression of M2 markers\u2014including Mgl1 and Mrc1\u2014and enhanced TGF\u03b2 secretion were found in na\u00efve BMDMs extracted from NLRX1 KO mice, indicating functional polarization towards the pro-fibrotic M2 subtype. NLRX1 KO na\u00efve macrophages also showed a significantly enhanced oxygen consumption rate compared to WT cells and increased basal respiration and maximal respiration capacities that equal the level of M2-polarized macrophages. In vivo, we found that NLRX1 KO mice presented enhanced M2 polarization markers together with enhanced tubular injury and fibrosis demonstrated by augmented TGF\u03b2 levels, fibronectin, and collagen accumulation. Conclusions: Our findings highlight the unique role of NLRX1 in regulating the metabolism and function of macrophages, ultimately protecting against excessive renal injury and fibrosis in UUO.<\/jats:p>","DOI":"10.3390\/cells13010023","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T03:36:17Z","timestamp":1703129777000},"page":"23","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["NLRX1 Prevents M2 Macrophage Polarization and Excessive Renal Fibrosis in Chronic Obstructive Nephropathy"],"prefix":"10.3390","volume":"13","author":[{"given":"Ye","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China"},{"name":"Department of Pathology, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotte","family":"Kors","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loes M.","family":"Butter","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3280-6311","authenticated-orcid":false,"given":"Geurt","family":"Stokman","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nike","family":"Claessen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8361-2448","authenticated-orcid":false,"given":"Coert J.","family":"Zuurbier","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen E.","family":"Girardin","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaklien C.","family":"Leemans","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Florquin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3128-5259","authenticated-orcid":false,"given":"Alessandra","family":"Tammaro","sequence":"additional","affiliation":[{"name":"Department of Pathology, Amsterdam Infection & Immunity, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1172\/JCI31487","article-title":"Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases","volume":"117","author":"Wynn","year":"2007","journal-title":"J. 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