Chapter 20 : The Functional Heterogeneity of Activated Macrophages

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New and improved ways to phenotype cells in tissue have led to a better understanding of the heterogeneity of activated macrophages. Macrophages are derived from progenitor cells in the bone marrow. Once in tissue, macrophages can undergo profound physiological changes in response to the combination of cytokines and inflammatory stimuli they encounter there. Apoptotic cells are efficiently eliminated by macrophages through phagocytosis. This process can result in the production of transforming growth factor-β (TGF-β) by macrophages, a cytokine that is well known as a strong suppressor of T-cell activation and antibody secretion by B cells. Adenosine is a purine nucleoside that can accumulate in the extracellular space following stress or inflammation. Macrophages have four adenosine receptors, A1, A2A, A2B, and A3, all of which are seven-transmembrane, G-protein- coupled receptors (GPCRs). Macrophage-stimulating protein (MSP), also known as hepatocyte growth factor-like (HGFL), is a plasma protein belonging to the plasminogen-related growth factor (PRGF) family. Treatment of macrophages with glucocorticoids (GCs) has a profound inhibitory effect on the production of proinflammatory cytokines, including tumor necrosis factor (TNF) and interleukin-12 (IL-12). This inhibition can skew immune responses toward a Th2 response and prevent macrophage-mediated inflammation. The Toll-like receptor (TLR) pathway represents an activating avenue that has the potential to lead to new adjuvants and better vaccines. Conversely, the uncovering of the signaling pathway leading to IL-10 overproduction has the potential to lead to a novel class of anti-inflammatory compounds that induce IL-10 production from macrophages.

Citation: Zhang X, Mosser D. 2009. The Functional Heterogeneity of Activated Macrophages, p 325-340. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch20

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Image of FIGURE 1

IL-10 cytokine production from macrophages following differential priming and stimulation. Macrophages were primed overnight with either 100 U/ml IFN-γ (black bars) or 10 U/ml IL-4 (gray bars). The next morning, cells were stimulated with either 10 ng/ml of lipopolysaccharide alone (LPS) or LPS plus immune complexes consisting of OVA:anti-OVA (LPS+IC). Some cells received no stimulation (NS). After 18 h, IL-10 in supernatants was measured by ELISA. No detectable IL-10 was found in unstimulated cells regardless of the priming. Macrophages primed with IL-4 made more IL-10 in response to LPS than did classically activated (IFN-γ-primed) macrophages. Cells stimulated with LPS in the presence of IC made substantially more IL-10, regardless of how they were primed.

Citation: Zhang X, Mosser D. 2009. The Functional Heterogeneity of Activated Macrophages, p 325-340. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch20
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Image of FIGURE 2

T-cell proliferation in response to antigen presented by different populations of macrophages. Macrophages were primed overnight with IL-4 (top two panels) or IFN-γ (bottom panel). The following morning, 150 μg/ml OVA was added to each population. Macrophages in the top panel received OVA alone. Macrophages in the middle and bottom panels received OVA along with 10 ng/ml LPS. After 96 h of coculture with carboxyfluorescein diacetate, the proliferation of succinimidyl ester (CFSE)-labeled CD4 T cells from DO11.10 mice was measured by the dilution of CFSE. IL-4-primed macrophages (top panel) support only modest T-cell proliferation, and the addition of LPS to stimulate IL-4-primed macrophages (middle panel) does not enhance their ability to present antigen. Mφ-II (bottom panel) readily induce T-cell proliferation as evidenced by the high degree of CFSE dilution.

Citation: Zhang X, Mosser D. 2009. The Functional Heterogeneity of Activated Macrophages, p 325-340. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch20
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Image of FIGURE 3

Antibody production in DO11.10 mice after immunization with OVA along with different macrophage populations. Macrophages from BALB/c mice were activated in vitro with LPS alone (Type 1 Mφ) or LPS plus an irrelevant immune complex, E-IgG (Type 2 Mφ). One hour after activation, 2 × 10 Mφ were injected intraperitoneally into mice along with 50 μg of OVA in the absence of adjuvant. This procedure was repeated 10 days later. Nine days after the second immunization, mice were bled, and OVA-specific antibody (Ig) (black bars), IgG1 (open bars), and IgG2a (dark gray bars) were measured by ELISA (* < 0.05; ** < 0.01).

Citation: Zhang X, Mosser D. 2009. The Functional Heterogeneity of Activated Macrophages, p 325-340. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch20
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