Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Subject Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Program
    • Feedback
    • Reprints
    • Impact Factor
  • ASN Kidney News
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • CJASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Subject Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Program
    • Feedback
    • Reprints
    • Impact Factor
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
Up Front MattersEditorials
You have accessRestricted Access

Macrophages in Kidney Repair and Regeneration

Jeremy S. Duffield
JASN February 2011, 22 (2) 199-201; DOI: https://doi.org/10.1681/ASN.2010121301
Jeremy S. Duffield
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • View PDF
Loading

Appreciation of a central role for recruited monocyte-derived macrophages to repair organs after injury is gaining considerable momentum. In the past 2 years, monocyte-derived tissue leukocytes have been identified as orchestrators of repair in skin, muscle, gut, brain, and heart. Macrophages, however, exhibit considerable plasticity in their phenotype and can polarize into functional states that additionally contribute to tissue injury or fibrosis. These functional states have become known as M1 for pro-injurious functions and M2 for wound-healing functions, but this nomenclature belies the complexity of macrophage diversity. The phenotypic switch that is central to macrophage-directed repair and the effectors of this repair merit further study.

In kidney diseases, monocyte-derived tissue effector cells, known as macrophages, have a bad reputation along with neutrophils as drivers of tissue injury and fibrosis.1 Although this is certainly true and therapies that target injurious macrophages and injurious mechanisms of the innate immune system that wreak havoc inappropriately in our organs are greatly welcomed, it seems that proinflammatory macrophages and neutrophils are the exception that proves the rule.1,2.

What is the rule? The innate immune system serves to police our organs and promote repair and regeneration without causing injury. Only in overwhelming circumstances such as infection or severe tissue injury do macrophages activate sterilizing and injurious programs. Macrophages are particularly adept at clearing debris, extracellular matrix, immune complexes, and dead cell products of tissue injury and most of the time perform such tasks silently.3 The same sort of macrophages also seem to have the capacity to release almost every cytokine and growth factor described in the literature. Coordinated release of many of these factors promotes organized tissue regeneration including basement membrane synthesis, cell proliferation, cell migration, and dampening of the inflammatory response.

In some circles, reparative monocyte-derived cells with avidity for microvascular repair are known as endothelial progenitor cells (EPCs). EPCs are now widely described to promote capillary repair and restoration by a number of mechanisms, including canalization of new capillary tracts, temporary (days to weeks) replacement of endothelial cells in areas of denuded capillary basement membrane, new capillary basement membrane synthesis, cytokine release that promotes endothelial cell proliferation, and adoption of pericyte functions.4,5

But can the endogenous reparative functions of macrophages be harnessed for good in the kidney? It seems so. Lee et al.2 in this issue of JASN set out to test whether deliberate manipulation of inflammatory monocyte/macrophages alters the course of injury and repair in kidney ischemia reperfusion injury (IRI). In loss-of-function studies, the authors specifically ablate monocytes and macrophages using a toxic drug encapsulated within liposomes. Ablation at the onset of injury was protective, whereas ablation during the repair phase was deleterious. In gain-of-function studies, they adoptively transferred into the circulation macrophages that were recruited to the injured kidney. Macrophages primed with IFN-γ to adopt an M1 or injurious phenotype exacerbated injury, but adoptively transferred macrophages primed to exhibit a wound-healing phenotype lacked this capacity. Typical macrophage M1 markers such as nitric oxide synthase 2 were found in early kidney injury, whereas typical macrophage M2 markers such as the mannose receptor were detected during the repair phase. When the investigators adoptively transferred M1-primed macrophages to the kidney early after injury and then tracked them, they noted the transferred cells activated the M2 markers, the mannose receptor, and Arginase with time, indicative of a phenotypic switch.

M2-primed macrophages had a specific capacity to stimulate tubular cell proliferation in vitro and in vivo. Thus, during the normal repair of kidney injured by ischemia, macrophages acquire regenerative functions, which included stimulating successful epithelial proliferation.

These findings are entirely consistent with several other studies published in the past year in which macrophages or the monocyte-derived dendritic cells were ablated during the repair phase of IRI in the kidney with deleterious outcomes.6–8 These other studies used a genetic system to ablate macrophages, which has significant methodologic differences compared with the report from Lee et al.2 Nevertheless, the consistent message is that macrophages promote normal repair and regeneration after injury, and a major component of that process is stimulation of epithelial regeneration by cell–cell cross-talk.

In none of these studies or the study by Lee et al.,2 however, has the role of macrophages in repair of the capillaries of regenerating kidney been studied, yet the parallels between monocyte-derived EPCs in microvascular repair and macrophages in epithelial repair are striking, and vital peritubular capillaries are severely disrupted in ischemic kidney injury.9 In models of single toxic, ischemic, or surgical injury of heart, skeletal muscle, gut, pancreas, liver, brain, and skin, a wave of repairing monocyte-derived cells moves into the tissue and orchestrates a repair and regeneration program.4,10–14 This suggests the observations in kidney repair reflect a generalized function of the macrophage, one that can be harnessed for therapeutic benefit.

What next? Although we now know that macrophages can promote repair, the studies of Lee et al.2 tell us this occurs at the expense of M1 activation followed by a phenotypic switch and that M1-activated macrophages can be deleterious. With the advent of cell therapy, it may be possible to administer primed monocytes to the circulation that do not require M1 activation to deliver regenerative functions to the kidney. Studies of this nature (IL-10–expressing adoptively transferred macrophages) were performed nearly 10 years ago in the laboratory of David Kluth and Andy Rees in rat models of glomerulonephritis, but, although convincing, this line of investigation never made it to human studies.15 Perhaps we should revisit this as a therapeutic strategy.

It is clear that while in the experimental tissue milieu of post-IRI kidney macrophages cause repair in rodents, this environment may not often be present in human disease, and many studies of rodents show that macrophages in chronic renal injury actually drive injury and fibrosis.1 Understanding which tissue factors trigger a phenotypic switch toward tissue repair and regeneration and the macrophage effectors that bring about repair and regeneration may bear more therapeutic fruit for humans in need of macrophage-directed therapy in the future. To that end, several studies now implicate successful delivery of the macrophage cytokine IL-10 to the kidney or stimulation of macrophage Wnt signaling pathways in epithelium as potential therapeutic options for human disease.6,16

DISCLOSURES

None.

Acknowledgments

The Laboratory of Inflammation Research is supported by National Institutes of Health grants DK73299, DK84077, and DK87389; University of Washington; Genzyme GRIP award; and an award from Regulus Inc.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

  • See related article, “Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair,” on pages 317–326.

  • Copyright © 2011 by the American Society of Nephrology

REFERENCES

  1. 1.↵
    1. Duffield JS
    : Macrophages and immunologic inflammation of the kidney. Semin Nephrol 30: 234–254, 2010
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Lee S,
    2. Huen S,
    3. Nishio H,
    4. Nishio S,
    5. Lee HK,
    6. Choi B-S,
    7. Ruhrberg C,
    8. Cantley LG
    : Distinct macrophage phenotypes contribute to kidney injury and repair. J Am Soc Nephrol 22: 323–332, 2011
    OpenUrl
  3. 3.↵
    1. Meszaros AJ,
    2. Reichner JS,
    3. Albina JE
    : Macrophage phagocytosis of wound neutrophils. J Leukoc Biol 65: 35–42, 1999
    OpenUrlPubMed
  4. 4.↵
    1. Glod J,
    2. Kobiler D,
    3. Noel M,
    4. Koneru R,
    5. Lehrer S,
    6. Medina D,
    7. Maric D,
    8. Fine HA
    : Monocytes form a vascular barrier and participate in vessel repair after brain injury. Blood 107: 940–946, 2006
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Jujo K,
    2. Hamada H,
    3. Iwakura A,
    4. Thorne T,
    5. Sekiguchi H,
    6. Clarke T,
    7. Ito A,
    8. Misener S,
    9. Tanaka T,
    10. Klyachko E,
    11. Kobayashi K,
    12. Tongers J,
    13. Roncalli J,
    14. Tsurumi Y,
    15. Hagiwara N,
    16. Losordo DW
    : CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction. Proc Natl Acad Sci U S A 107: 11008–11013, 2010
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Lin SL,
    2. Li B,
    3. Rao S,
    4. Yeo EJ,
    5. Hudson TE,
    6. Nowlin BT,
    7. Pei H,
    8. Chen L,
    9. Zheng JJ,
    10. Carroll TJ,
    11. Pollard JW,
    12. McMahon AP,
    13. Lang RA,
    14. Duffield JS
    : Macrophage Wnt7b is critical for kidney repair and regeneration. Proc Natl Acad Sci U S A 107: 4194–4199, 2010
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Menke J,
    2. Iwata Y,
    3. Rabacal WA,
    4. Basu R,
    5. Yeung YG,
    6. Humphreys BD,
    7. Wada T,
    8. Schwarting A,
    9. Stanley ER,
    10. Kelley VR
    : CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice. J Clin Invest 119: 2330–2342, 2009
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Kim MG,
    2. Boo CS,
    3. Ko YS,
    4. Lee HY,
    5. Cho WY,
    6. Kim HK,
    7. Jo SK
    : Depletion of kidney CD11c+ F4/80+ cells impairs the recovery process in ischaemia/reperfusion-induced acute kidney injury. Nephrol Dial Transplant 25: 2908–2921, 2010
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Li B,
    2. Cohen A,
    3. Hudson TE,
    4. Motlagh D,
    5. Amrani DL,
    6. Duffield JS
    : Mobilized human hematopoietic stem/progenitor cells promote kidney repair after ischemia/reperfusion injury. Circulation 121: 2211–2220, 2010
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Nahrendorf M,
    2. Swirski FK,
    3. Aikawa E,
    4. Stangenberg L,
    5. Wurdinger T,
    6. Figueiredo JL,
    7. Libby P,
    8. Weissleder R,
    9. Pittet MJ
    : The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 204: 3037–3047, 2007
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Arnold L,
    2. Henry A,
    3. Poron F,
    4. Baba-Amer Y,
    5. van Rooijen N,
    6. Plonquet A,
    7. Gherardi RK,
    8. Chazaud B
    : Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med 204: 1057–1069, 2007
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Duffield JS,
    2. Forbes SJ,
    3. Constandinou CM,
    4. Clay S,
    5. Partolina M,
    6. Vuthoori S,
    7. Wu S,
    8. Lang R,
    9. Iredale JP
    : Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115: 56–65, 2005
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Mirza R,
    2. DiPietro LA,
    3. Koh TJ
    : Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol 175: 2454–2462, 2009
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Pull SL,
    2. Doherty JM,
    3. Mills JC,
    4. Gordon JI,
    5. Stappenbeck TS
    : Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc Natl Acad Sci U S A 102: 99–104, 2005
    OpenUrlAbstract/FREE Full Text
  15. 15.↵
    1. Wilson HM,
    2. Stewart KN,
    3. Brown PA,
    4. Anegon I,
    5. Chettibi S,
    6. Rees AJ,
    7. Kluth DC
    : Bone-marrow-derived macrophages genetically modified to produce IL-10 reduce injury in experimental glomerulonephritis. Mol Ther 6: 710–717, 2002
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Mu W,
    2. Ouyang X,
    3. Agarwal A,
    4. Zhang L,
    5. Long DA,
    6. Cruz PE,
    7. Roncal CA,
    8. Glushakova OY,
    9. Chiodo VA,
    10. Atkinson MA,
    11. Hauswirth WW,
    12. Flotte TR,
    13. Rodriguez-Iturbe B,
    14. Johnson RJ
    : IL-10 suppresses chemokines, inflammation, and fibrosis in a model of chronic renal disease. J Am Soc Nephrol 16: 3651–3660, 2005
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 22 (2)
Journal of the American Society of Nephrology
Vol. 22, Issue 2
1 Feb 2011
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in JASN.
Enter multiple addresses on separate lines or separate them with commas.
Macrophages in Kidney Repair and Regeneration
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Macrophages in Kidney Repair and Regeneration
Jeremy S. Duffield
JASN Feb 2011, 22 (2) 199-201; DOI: 10.1681/ASN.2010121301

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Macrophages in Kidney Repair and Regeneration
Jeremy S. Duffield
JASN Feb 2011, 22 (2) 199-201; DOI: 10.1681/ASN.2010121301
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • DISCLOSURES
    • Acknowledgments
    • Footnotes
    • REFERENCES
  • Info & Metrics
  • View PDF

More in this TOC Section

Up Front Matters

  • Sphingosine-1-Phosphate Metabolism and Signaling in Kidney Diseases
  • COVID-19–Associated Acute Kidney Injury: Learning from the First Wave
  • Will Targeting Interleukin-6 in the Anemia of CKD Change Our Treatment Paradigm?
Show more Up Front Matters

Editorials

  • The Road Ahead for Research on Air Pollution and Kidney Disease
  • Missing Self and DSA—Synergy of Two NK Cell Activation Pathways in Kidney Transplantation
  • Animal Model of Pregnancy after Acute Kidney Injury Mirrors the Human Observations
Show more Editorials

Cited By...

  • Kidney Single-Cell Atlas Reveals Myeloid Heterogeneity in Progression and Regression of Kidney Disease
  • Kidney single-cell atlas reveals myeloid heterogeneity in progression and regression of kidney disease
  • Tamm-Horsfall Protein Regulates Mononuclear Phagocytes in the Kidney
  • Autocrine IL-10 activation of the STAT3 pathway is required for pathological macrophage differentiation in polycystic kidney disease
  • Cross-Species Transcriptional Network Analysis Defines Shared Inflammatory Responses in Murine and Human Lupus Nephritis
  • Google Scholar

Similar Articles

Related Articles

  • Distinct Macrophage Phenotypes Contribute to Kidney Injury and Repair
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Annual Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire