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Cited by 968Immune cells in cancerPhagocytosis and Immune RegulationCardiac Fibrosis and Remodeling

Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences

Stout, Robert D, Jiang, Chuancang, Matta, Bharati, Tietzel, Illya, Watkins, Stephanie K, Suttles, Jill·2005·The Journal of Immunology
DOI 10.4049/jimmunol.175.1.342
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Abstract

Recent studies have described the development of distinct functional subsets of macrophages in association with cancer, autoimmune disease, and chronic infections. Based on the ability of Th1 vs Th2 cytokines to promote opposing activities in macrophages, it has been proposed that macrophages develop into either type 1 inflammatory or type 2 anti-inflammatory subsets. As an alternative to the concept of subset development, we propose that macrophages, in response to changes in their tissue environment, can reversibly and progressively change the pattern of functions that they express. As demonstrated herein, macrophages can reversibly shift their functional phenotype through a multitude of patterns in response to changes in cytokine environment. Macrophages display distinct functional patterns after treatment with IFN-γ, IL-12, IL-4, or IL-10 and additional functional patterns are displayed depending on whether the cytokine is present alone or with other cytokines and whether the cytokines are added before or concomitantly with the activating stimulus (LPS). Sequential treatment of macrophages with multiple cytokines results in a progression through multiple functional phenotypes. This ability to adapt to changing cytokine environments has significant in vivo relevance, as evidenced by the demonstration that macrophage functional phenotypes established in vivo in aged or tumor-bearing mice can be altered by changing their microenvironment. A concept of functional adaptivity is proposed that has important implications for therapeutic targeting of macrophages in chronic diseases that result in the dominance of particular functional phenotypes of macrophages that play a significant role in disease pathology.

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  • Macrophages switch polarization states in response to their microenvironment.

    “Unlike terminally differentiated cells, macrophages switch polarization states in response to their microenvironment.This is emphasized by the contrasting gene expression during early and late stages of the FBR [24], as well as their ability to adapt functionality in response to the temporal presentation of stimuli [25].”

    From Biomaterial based modulation of macrophage polarization: a review and suggested design principles (2015) · cites this paper as [24]

  • LPS-stimulated classically activated macrophages become TLR-tolerant and unable to produce similarly elevated pro-inflammatory cytokines upon second LPS exposure, but retain ability to produce anti-inflammatory cytokines like IL-10.

    “For example, in vitro experiments have shown that LPS stimulated, classically activated macrophages, become Toll-like receptor (TLR)-tolerant and unable to produce similarly elevated levels of pro-inflammatory cytokines upon second exposure to LPS [16–18].”

    From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [16]

  • Macrophages have dynamic and plastic phenotypes that change with local microenvironmental signals, unlike lymphocytes whose phenotype is relatively fixed upon differentiation.

    “It has been shown that unlike lymphocytes, where cellular phenotype is relatively fixed upon differentiation, macrophages have dynamic and plastic phenotypes that change with local microenvironmental signals [5,14–16].”

    From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [16]

  • A comprehensive in vivo macrophage phenotype cannot be deduced solely from a limited set of phenotypic markers.

    “Additionally, a comprehensive in vivo Mp phenotype cannot be deduced solely from a limited set of phenotypic markers, as different M2a-associated genes or proteins can exhibit entirely different temporal regulation and can be coexpressed with M1-associated markers [19,25,33,60,78].”

    From Macrophage phenotypes during tissue repair (2013) · cites this paper as [19]

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Authors
Stout, R. D., Jiang, C., Matta, B., Tietzel, I., Watkins, S. K., & Suttles, J.
Affiliations
University of Louisville (US)
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2005-07-01
Volume
175
Issue
1
Pages
342-349
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.175.1.342
OpenAlex
W2121438383
Cited by
968
References
50
Citations by year
2026: 9 · 2025: 24 · 2024: 31 · 2023: 54 · 2022: 54 · 2021: 61 · 2020: 42 · 2019: 36 · 2018: 64 · 2017: 59 · 2016: 61 · 2015: 72 · 2014: 78 · 2013: 78 · 2012: 60
FWCI
8.32
Type
journal article
Language
en
Open access
closed
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ag020972-04)
  • National Institute on Aging (R01 AG020972-02, AG20972, R01 AG020972-01A1)
  • National Institute of Allergy and Infectious Diseases (R01AI048850, AI48850)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
Keywords
macrophage polarization, cytokine environment, Th1/Th2 cytokines, interferon-gamma, IL-12, IL-4, IL-10, lipopolysaccharide, tumor-bearing mice, aged mice, chronic disease, macrophage-targeted therapy
MeSH terms
Animals, Arginase, Environment, Female, Interferon-gamma, Ligands, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Mice, Inbred DBA, Neoplasms, Experimental, Phenotype, Prostaglandin-Endoperoxide Synthases, Recombinant Proteins, Interleukin-4, Cytokines, Interleukin-10, Interleukin-12, Nitric Oxide Synthase, Mice, Cyclooxygenase 2, Nitric Oxide Synthase Type II

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