Distinct macrophage phenotypes contribute to kidney injury and repair
Open accessAbstract
The ischemically injured kidney undergoes tubular cell necrosis and apoptosis, accompanied by an interstitial inflammatory cell infiltrate. In this study, we show that iNos-positive proinflammatory (M1) macrophages are recruited into the kidney in the first 48 hours after ischemia/reperfusion injury, whereas arginase 1- and mannose receptor-positive, noninflammatory (M2) macrophages predominate at later time points. Furthermore, depletion of macrophages before ischemia/reperfusion diminishes kidney injury, whereas depletion at 3 to 5 days after injury slows tubular cell proliferation and repair. Infusion of Ifnγ-stimulated, bone marrow-derived macrophages into macrophage-depleted mice at the time of kidney reperfusion restored injury to the level seen without macrophage depletion, suggesting that proinflammatory macrophages worsen kidney damage. In contrast, the appearance of macrophages with the M2 phenotype correlated with the proliferative phase of kidney repair. In vitro studies showed that IFNγ-stimulated, proinflammatory macrophages begin to express markers of M2 macrophages when cocultured with renal tubular cells. Moreover, IL-4-stimulated macrophages with an M2 phenotype, but not IFNγ-stimulated proinflammatory macrophages, promoted renal tubular cell proliferation. Finally, tracking fluorescently labeled, IFNγ-stimulated macrophages that were injected after injury showed that inflammatory macrophages can switch to an M2 phenotype in the kidney at the onset of kidney repair. Taken together, these studies show that macrophages undergo a switch from a proinflammatory to a trophic phenotype that supports the transition from tubule injury to tubule repair.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In mouse kidney ischemia-reperfusion injury, Mp expression of iNOS mRNA is highest at 1-day postinjury and subsequently declines.
“In mouse kidney ischemia-reperfusion injury, Mp expression of iNOS mRNA is highest at 1-day postinjury and subsequently declines, consistent with an early M1 phenotype [63].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [63]
In mouse and human skin wounds and in injured mouse kidney, Mp expression of CD206 increases during the later stages of repair.
“Indeed, in mouse and human skin wounds and in injured mouse kidney, Mp expression of CD206 increases during the later stages of repair [33,60,61,63].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [63]
The M1-associated cytokines IL-1β, TNF-α, IL-6, and IL-12 are expressed by Mp during the first few hours to days after acute injury in numerous tissues, including skin, liver, kidney, and skeletal muscle.
“The M1-associated cytokines IL-1, TNF-␣, IL-6, and IL-12 are expressed by Mp during the first few hours to days after acute injury in numerous tissues, including skin [33,60,61], liver [62], kidney [63], and skeletal muscle [57,64].”
From Macrophage phenotypes during tissue repair (2013) · cites this paper as [63]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The chemokine system in diverse forms of macrophage activation and polarization
MANTOVANI, A., SICA, A., SOZZANI, S., ALLAVENA, P., VECCHI, A., & LOCATI, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.09.015 · Cited by 6,534 · see citing works
Alternative Activation of Macrophages: An Immunologic Functional Perspective
Martinez, F. O., Helming, L., & Gordon, S. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132532 · Cited by 2,745 · see citing works
Fibrotic disease and the TH1/TH2 paradigm
Wynn, T. A. (2004) · Nature Reviews Immunology · doi:10.1038/nri1412 · Cited by 1,765 · see citing works
Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury.
Kelly, K. J., Williams, W. W., Colvin, R. B., Meehan, S. M., Springer, T. A., Gutierrez‐Ramos, J. C., & Bonventre, J. V. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118498 · Cited by 733 · see citing works
Macrophage diversity in renal injury and repair
Ricardo, S. D., van Goor, H., & Eddy, A. A. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36150 · Cited by 726 · see citing works
Bone marrow stem cells contribute to repair of the ischemically injured renal tubule
Kale, S., Karihaloo, A. K., Clark, P. R., Kashgarian, M. J., Krause, D. S., & Cantley, L. G. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17856 · Cited by 546 · see citing works
Self-citationThe Morphology of “Acute Tubular Necrosis” in Man
Solez, K., Morel-Marogér, L., & Sraer, J. (1979) · Medicine · doi:10.1097/00005792-197909000-00003 · Cited by 468 · see citing works
Differential expression of FIZZ1 and Ym1 in alternatively versus classically activated macrophages
Raes, G., BAETSELIER, P. D., Noël, W., Beschin, A., Brombacher, F., & Gh., G. H. (2002) · Journal of Leukocyte Biology · doi:10.1189/jlb.71.4.597 · Cited by 443 · see citing works
Macrophage Wnt7b is critical for kidney repair and regeneration
Lin, S., Li, B., Rao, S., Yeo, E.-J., Hudson, T. E., Nowlin, B. T., Pei, H., Chen, L., Zheng, J., Carroll, T. J., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0912228107 · Cited by 424 · see citing works
Ginderachter, J. A. V., Movahedi, K., Ghassabeh, G. H., Meerschaut, S., Beschin, A., Raes, G., & BAETSELIER, P. D. (2006) · Immunobiology · doi:10.1016/j.imbio.2006.06.002 · Cited by 370 · see citing works
Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease
Wang, Y., Wang, Y. P., Zheng, G., Lee, V. W., Ouyang, L., Chang, D. H. H., Mahajan, D., Coombs, J., Wang, Y., Alexander, S. I., et al. (2007) · Kidney International · doi:10.1038/sj.ki.5002275 · Cited by 369 · see citing works
Dong, X., Swaminathan, S., Bachman, L. A., Croatt, A. J., Nath, K. A., & Griffin, M. D. (2007) · Kidney International · doi:10.1038/sj.ki.5002132 · Cited by 363 · see citing works
Noben-Trauth, N., Shultz, L. D., Brombacher, F., Urban, J. F., Gu, H., & Paul, W. E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.20.10838 · Cited by 344 · see citing works
Day, Y., Huang, L., Ye, H., Linden, J. M., & Okusa, M. D. (2004) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00378.2004 · Cited by 331 · see citing works
Macrophages contribute to the initiation of ischaemic acute renal failure in rats
Jo, S.-K., Sung, S.-A., Cho, W.-Y., Go, K.-J., & Kim, H. K. (2006) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfk047 · Cited by 327 · see citing works
DIBLE, J. H., Gm, B., & DARMADY, E. M. (1950) · PubMed · Cited by 308 · see citing works
Barner, M., Mohrs, M., Brombacher, F., & Köpf, M. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70256-8 · Cited by 208 · see citing works
Miura, M., Fu, X., Zhang, Q.-W., Remick, D. G., & Fairchild, R. L. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63065-9 · Cited by 204 · see citing works
T cells as mediators in renal ischemia/reperfusion injury
Ysebaert, D., Greef, K. E. D., Beuf, A. D., Rompay, A. R. V., Vercauteren, S., Persy, V. P., & Broe, M. E. D. (2004) · Kidney International · doi:10.1111/j.1523-1755.2004.761_4.x · Cited by 190 · see citing works
CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice
Weinmann‐Menke, J., Iwata, Y., Rabacal, W., Basu, R., Yeung, Y.-G., Humphreys, B. D., Wada, T., Schwarting, A., Stanley, E. R., & Kelley, V. R. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39087 · Cited by 171 · see citing works
Differential Macrophage Activation Alters the Expression Profile of NTPDase and Ecto-5′-Nucleotidase
Zanin, R. F., Braganhol, E., Bergamin, L. S., Campesato, L. F., Zanotto‐Filho, A., Moreira, J. C. F., Morrone, F. B., Sévigny, J., Schetinger, M. R. C., Wyse, Â. T. D. S., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0031205 · Cited by 157 · see citing works
Macrophage involvement in the kidney repair phase after ischaemia/reperfusion injury
Vinuesa, E., Hotter, G., Jung, M., Herrero, I., Torrás, J., & Solà, A. (2007) · The Journal of Pathology · doi:10.1002/path.2259 · Cited by 133 · see citing works
Effects of cyclosporin A on the development of immune-mediated interstitial nephritis
Shih, W. Y., Hines, W. H., & Neilson, E. G. (1988) · Kidney International · doi:10.1038/ki.1988.119 · Cited by 121 · see citing works
The intracellular domain of CD44 promotes the fusion of macrophages
Cui, W. (2006) · Blood · doi:10.1182/blood-2005-05-1902 · Cited by 110 · see citing works
Role of the T-cell receptor in kidney ischemia–reperfusion injury
Savransky, V., Molls, R. R., Burne-Taney, M. J., et al. (2006) · Kidney International · doi:10.1038/sj.ki.5000038 · Cited by 107 · see citing works
Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13
Wynes, M. W., & Riches, D. W. H. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.7.3550 · Cited by 105 · see citing works
Pathophysiology of Acute Kidney Injury: Roles of Potential Inhibitors of Inflammation
Bonventre, J. V. (2007) · KARGER eBooks · doi:10.1159/000102069 · Cited by 89 · see citing works
A simplified method for isolation of large numbers of defined nephron segments
Schafer, J. A., Watkins, M. L., Li, L., et al. (1997) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.1997.273.4.f650 · Cited by 85 · see citing works
Sinha, D., Wang, Z., Price, V. R., et al. (2003) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00172.2002 · Cited by 81 · see citing works
Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells.
Beck‐Schimmer, B., Oertli, B., Pasch, T., & Wuthrich, R. P. (1998) · Journal of the American Society of Nephrology · doi:10.1681/asn.v9122283 · Cited by 79 · see citing works
Blocking the immune response in ischemic acute kidney injury: the role of adenosine 2A agonists
Li, L., & Okusa, M. D. (2006) · Nature Reviews Nephrology · doi:10.1038/ncpneph0238 · Cited by 77 · see citing works
Macrophages in Kidney Repair and Regeneration
Duffield, J. S. (2011) · Journal of the American Society of Nephrology · doi:10.1681/asn.2010121301 · Cited by 50 · see citing works
Immunohistochemical manifestations of unilateral kidney ischemia
Ibrahim, S., Jacobs, F., Zukin, Y., et al. (1996) · Clinical Transplantation · doi:10.1111/j.1399-0012.1996.tb00763.x · Cited by 46 · see citing works
HGF promotes adhesion of ATP-depleted renal tubular epithelial cells in a MAPK-dependent manner
Liu, Z., Nickel, C. H., & Cantley, L. G. (2001) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.2001.281.1.f62 · Cited by 33 · see citing works
Self-citationBakker, J., Sanders, A., & van Rooijen, N. (1998) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/s0005-2736(98)00089-3 · Cited by 12 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [18]18. Wynn TA: Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol 4: 583–594, 2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
Cited by
Sorted by citations
Macrophage phenotypes during tissue repair
Novak, M. L., & Koh, T. J. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.1012512 · Cited by 658 · see citing works
Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease
Prame Kumar, K., Nicholls, A. J., & Wong, C. H. Y. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2753-2 · Cited by 417 · see citing works
Chistiakov, D. A., Myasoedova, V. A., Revin, V. V., Orekhov, A. N., & Bobryshev, Y. V. (2018) · Immunobiology · doi:10.1016/j.imbio.2017.10.005 · Cited by 311 · see citing works
Immune cells and inflammation in AKI to CKD progression
Sato, Y., & Yanagita, M. (2018) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00195.2018 · Cited by 273 · see citing works
Unraveling macrophage contributions to bone repair
Wu, A. C., Raggatt, L. J., Alexander, K. A., & Pettit, A. R. (2013) · BoneKEy Reports · doi:10.1038/bonekey.2013.107 · Cited by 256 · see citing works
Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis
Bhatia, D., Chung, K.-P., Nakahira, K., Patino, E., Rice, M. C., Torres, L. K., Muthukumar, T., Choi, A. M. K., Akchurin, O. M., & Choi, M. E. (2019) · JCI Insight · doi:10.1172/jci.insight.132826 · Cited by 185 · see citing works
Macrophages are critical to the maintenance of IL-13-dependent lung inflammation and fibrosis
Borthwick, L. A., Barron, L., Hart, K. M., Vannella, K. M., Thompson, R. W., Oland, S., Cheever, A., Sciurba, J., Ramalingam, T. R., Fisher, A. J., et al. (2016) · Mucosal Immunology · doi:10.1038/mi.2015.34 · Cited by 138 · see citing works
Immunology of the ageing kidney
Sato, Y., & Yanagita, M. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0185-9 · Cited by 126 · see citing works
Senescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease
Schroth, J., Thiemermann, C., & Henson, S. M. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.564461 · Cited by 59 · see citing works
- Authors
- Lee, S., Huen, S., Nishio, H., Nishio, S., Lee, H. K., Choi, B.-S., Ruhrberg, C., & Cantley, L. G.
- Affiliations
- Yale University (US)
- Health Sciences University of Hokkaido (JP)
- Hokkaido University (JP)
- Korea Advanced Institute of Science and Technology (KR)
- University College London (GB)
- Corresponding author
- Lee, Sik
- Huen, Sarah
- Nishio, Hitoshi
- Nishio, Saori
- Choi, Bum-Soon
- Cantley, Lloyd G.
- Venue
- Journal of the American Society of Nephrology
- Published
- 2011-02
- Volume
- 22
- Issue
- 2
- Pages
- 317-326
- ISSN
- 1046-6673 (ISSN-L)
- PMC
- PMC3029904
- OpenAlex
- W2110720586
- Cited by
- 906
- References
- 35
- Citations by year
- 2026: 41 · 2025: 70 · 2024: 52 · 2023: 46 · 2022: 73 · 2021: 52 · 2020: 59 · 2019: 79 · 2018: 70 · 2017: 45 · 2016: 60 · 2015: 78 · 2014: 62 · 2013: 52 · 2012: 47
- FWCI
- 44.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of the American Society of Nephrology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK066216, R01DK065109, DK66216, DK65109, T32DK007276)
- Topics
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- macrophage polarization, M1/M2 macrophages, renal ischemia-reperfusion injury, tubular repair, tubular cell proliferation, macrophage depletion, interferon-gamma, IL-4, inducible nitric oxide synthase, arginase-1, CD206, renal tubular necrosis, apoptosis, interstitial inflammation
- MeSH terms
- Animals, Interferon-gamma, Kidney, Kidney Tubules, Macrophage Activation, Macrophages, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Phenotype, Reperfusion Injury, Interleukin-4, Ki-67 Antigen, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
