M-1/M-2 Macrophages and the Th1/Th2 Paradigm
Abstract
Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-gamma or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-beta1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-gamma production, while BALB/c SCID macrophages increase TGF-beta production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.
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Polarized macrophages are broadly referred to as M1 or M2, mimicking Th1/Th2 nomenclature.
“Broadly, polarized macrophages are referred to as having either an M1 or an M2 phenotype, mimicking the Th1/Th2 nomenclature which has been described for T helper cells [10].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [10]
Macrophages are a heterogeneous cell population with different markers and functions.
“Macrophages, like the monocytes from which they derive, are a heterogeneous cell population each with different markers and functions [1,8–12].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [10]
ARG1 in myeloid cells mainly functions as an enzyme to hydrolyze arginine to produce ornithine as part of the urea cycle, which promotes tissue repair through generation of polyamines and collagens, and reduces nitric oxide production from inducible nitric oxide synthase through decreasing intracellular arginine availability.
“ARG1 in myeloid cells mainly functions as an enzyme to hydrolyze arginine to produce ornithine as part of the urea cycle, which both promotes tissue repair through generation of polyamines and collagens, and also reduces nitric oxide production from inducible nitric oxide synthase through decreasing intracellular arginine availability (76–78).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [77]
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Tidball, J. G., Flores, I., Welc, S. S., Wehling-Henricks, M., & Ochi, E. (2021) · Experimental Gerontology · doi:10.1016/j.exger.2020.111200 · Cited by 66 · see citing works
Macrophages in metabolic associated fatty liver disease
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miR-24 Regulates Macrophage Polarization and Plasticity
Afsar R. Naqvi, J. B. F., & Nares, S. (2015) · Journal of Clinical & Cellular Immunology · doi:10.4172/2155-9899.1000362 · Cited by 65 · see citing works
“Interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) are the most potent inducers of classical Mφ activation and production of these cytokines is the major route by which T helper (Th) subset 1 (Th1) cells enhance the antimicrobial capacity of Mφ [2].”
BackgroundMiki, S., Suzuki, J.-I., Takashima, M., Ishida, M., Kokubo, H., & Yoshizumi, M. (2021) · Scientific Reports · doi:10.1038/s41598-021-01866-3 · Cited by 58 · see citing works
Nagenborg, J., Goossens, P., Biessen, E. A. L., & Donners, M. M. P. C. (2017) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2017.10.005 · Cited by 50 · see citing works
Ikeda, Y., Watanabe, H., Shiuchi, T., Hamano, H., Horinouchi, Y., Imanishi, M., Goda, M., Zamami, Y., Takechi, K., Izawa-Ishizawa, Y., et al. (2020) · Diabetologia · doi:10.1007/s00125-020-05153-0 · Cited by 53 · see citing works
Serum Interferon-Gamma Level Is Associated with Drug-Naïve Major Depressive Disorder
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Lipid profiling of polarized human monocyte-derived macrophages
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Comorbidity of mental and physical disorders
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- Authors
- Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J., & Hill, A. M.
- Affiliations
- University of Minnesota (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2000-06
- Volume
- 164
- Issue
- 12
- Pages
- 6166-6173
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2163175900
- Cited by
- 3,287
- References
- 1
- Citations by year
- 2026: 159 · 2025: 238 · 2024: 269 · 2023: 253 · 2022: 291 · 2021: 302 · 2020: 258 · 2019: 191 · 2018: 157 · 2017: 156 · 2016: 160 · 2015: 138 · 2014: 115 · 2013: 67 · 2012: 73
- FWCI
- 8.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01gm050150-05, 5r01dk051495-02)
- National Institute of General Medical Sciences (5P01GM50150)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK51495)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- Th1/Th2 balance, nitric oxide, arginine metabolism, ornithine, TGF-β1, inducible nitric oxide synthase, arginase, macrophage activation, interferon-gamma, lipopolysaccharide, polyamines, SCID mice, nude mice
- MeSH terms
- Animals, Arginine, Cells, Cultured, Female, Lymphocyte Activation, Macrophage Activation, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Nude, Nitric Oxide, Species Specificity, Spleen, Immunophenotyping, Cytokines, Transforming Growth Factor beta, Mice, SCID, Macrophages, Peritoneal, Th1 Cells, Th2 Cells, Coculture Techniques, Mice
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