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Review
. 2015 May 5:6:212.
doi: 10.3389/fimmu.2015.00212. eCollection 2015.

Anatomy of a discovery: m1 and m2 macrophages

Charles Dudley Mills  1
Affiliations
Review

Anatomy of a discovery: m1 and m2 macrophages

Charles Dudley Mills. Front Immunol. .

Abstract

M1 and M2 macrophage-type responses kill or repair in vivo. The unique ability of macrophages to make these polar opposite type of responses provides primary host protection and maintains tissue homeostasis throughout the animal kingdom. In humans and other higher animals, M1 and M2-type macrophage responses also initiate and direct T cells/adaptive immunity to provide additional protection such as Th1 (cytotoxic) or Th2 (antibody-mediated) type responses. Hence, macrophages were renamed M1 and M2 to indicate the central role of macrophages/innate immunity in immune systems. These findings indicate that the long held notion that adaptive immunity controls innate immunity was backward: a sea change in understanding how immune responses occur. The clinical impact of M1/kill and M2/repair responses is immense playing pivotal roles in curing (or causing) many diseases including infections, cancer, autoimmunity, and atherosclerosis. How M1/M2 came to be is an interesting story that, like life, involved Direction, Determination, Discouragement, and Discovery.

Keywords: M1; M2; Th1/Th2; cancer; innate immunity; macrophages; wound.

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Figures

Figure 1
Figure 1
It is useful sometimes to recognize the obvious rather than look for more complicated explanations in science, or in life.
Figure 2
Figure 2
Injection of bovine serum albumin, chemically modified to be “positively charged,” into a mouse caused it to be retained longer at the site of injection, and stimulated a stronger T cell mediated immune response.
Figure 3
Figure 3
Macrophages have both iNOS and arginase enzymes that can convert arginine to NO or ornithine, respectively. Products of each reaction inhibit the opposing reaction, promoting preferential NO or ornithine production.
Figure 4
Figure 4
(A, C) Following wounding, there is a 1-2 day “burst” of killer NO (measured as Citrulline and NO2) in vivo, followed by (B, D) macrophages metabolizing arginine to the growth-promoting repair molecule, ornithine (and urea), as healing proceeds. From Ref. (14). Copyright 1990. The American Association.
Figure 5
Figure 5
(C, D) Macrophages in a growing tumor (naïve) make growth-promoting ornithine (and urea). (A, B) Macrophages in a rejecting tumor (immune) make killer NO (and citrulline). From Ref. (45). Copyright 1992. The American Association of Immunologists, Inc.
Figure 6
Figure 6
Dominant NO production by C57B/6 macrophages compared to Balb/c macrophages. Also, NO production is inversely proportional to macrophage TGF-β production. From Ref. (16). Copyright 2000. The American Association of Immunologists, Inc.
Figure 7
Figure 7
Macrophages from C57Bl/6 mice make M1-dominant (NO) responses while Balb/c are M2-dominant (ornithine). M1- or M2-dominant responses stimulate Th1- or Th2-type responses that can further amplify cellular/CTL and M1, or antibody-type and M2 responses. From Ref. (1) with permission from S. Karger AG, Basel.
Figure 8
Figure 8
Macrophages initiate and direct other immune responses. For example, M1-type responses (e.g., through IL-12 and antigen presentation) direct T cells to become cytolytic T cells and produce IFN-γ that further elevates M1 activity. In contrast, M2-type macrophages cause T cells to produce molecules like IL-4 and TGF-β that cause B cells to produce antibody and elevate M2 responses. From Ref. (1) with permission from S. Karger AG, Basel.
Figure 9
Figure 9
Cytokines and other molecules associated with M1/inhibit or M2/heal-type responses. Certain products (middle) have been associated with both M1 and M2-type responses and can be thought of as general “inflammatory” cytokines or factors. From Ref. (1) with permission from S. Karger AG, Basel.
Figure 10
Figure 10
Macrophages have four basic SHIP functions [sample, heal, inhibit and present (antigen)] that allow them to recognize pathogens or injury, and respond directly (or indirectly by presenting antigens) to engender responses that provide optimal host protection. From Ref. (1) with permission from S. Karger AG, Basel.
Figure 11
Figure 11
M1/inhibit or M2/heal-dominant macrophage responses (or mixtures) can each be beneficial or detrimental depending on the disease circumstance. For example, M1/Th1-dominant responses are required to fight many infections (left). But, M1/Th1 responses are also causative of destructive inflammatory conditions in the brain and in atherosclerosis (right).
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References

    1. Mills CD, Ley K. M1 and M2 macrophages: the chicken and the egg of immunity. J Innate Immun (2014) 6:716–26.10.1159/000364945 - DOI - PMC - PubMed
    1. Mosmann TR, Coffman RL. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol (1989) 46:111–4710.1016/S0065-2776(08)60652-5 - DOI - PubMed
    1. Scott P, Pearce E, Cheever AW, Coffman RL, Sher A. Role of cytokines and CD4+ T-cell subsets in the regulation of parasite immunity and disease. Immunol Rev (1989) 112:161–82.10.1111/j.1600-065X.1989.tb00557.x - DOI - PubMed
    1. Finkelman FD, Holmes J, Katona IM, Urban JF, Jr, Beckmann MP, Park LS, et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol (1990) 8:303–3310.1146/annurev.iy.08.040190.001511 - DOI - PubMed
    1. O’Garra A, Murphy KM. Role of cytokines in determining T-lymphocyte function. Curr Opin Immunol (1994) 6:458–66.10.1016/0952-7915(94)90128-7 - DOI - PubMed

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