Inflammation Macrophages Go Back to School

John F. Foley

Science Signaling, AAAS, Washington, DC 20005, USA

Macrophages, phagocytic cells whose functions are often determined by their environment, are generally divided into two main classes: Classically activated (M1) macrophages are proinflammatory and kill pathogens, and alternatively activated (M2) macrophages produce anti-inflammatory factors. Two groups investigated the involvement of the transcription factor NF-B in determining whether a macrophage develops an M1 or M2 phenotype. Hagemann et al. inhibited signaling of the inhibitor of B (IB) kinase β (IKKβ) in mouse bone marrow-derived macrophages (BMDMs) or tumor-associated macrophages (TAMs) through gene deletion or the expression of a dominant-negative IKKβ mutant; inhibition of IKKβ activity resulted in inhibition of NF-B signaling. Whereas coculture of wild-type BMDMs with ovarian cancer cells resulted in the expected generation of M2 macrophages, as assessed by cytokine production, coculture of ovarian cancer cells with IKKβ-deficient BMDMs or TAMs generated M1 cells. Western blotting analyses showed that the activity of the transcription factor signal transducer and activator of transcription 1 (STAT1) was higher in IKKβ-deficient macrophages than in wild-type macrophages. Transfer of IKKβ-deficient TAMs to mice that contained preestablished tumors resulted in a decrease in tumor burden compared with that in mice that received wild-type cells. This effect was associated with a change in the cytokine profile of the tumors, from anti-inflammatory in mice that received wild-type macrophages to proinflammatory in mice that received IKKβ-deficient macrophages. Fong et al. investigated IKKβ function in the context of a mouse model of lung infection by Streptococcus pneumoniae. Whereas specific deletion of Ikkβ in airway epithelial cells resulted in both reduced inflammation and clearance of bacteria compared with that in wild-type mice, deletion of Ikkβ in macrophages resulted in enhanced bacterial clearance and prolonged inflammation. Consistent with the other study, the effects seen in mice with macrophage-specific Ikkβ deficiency were associated with the increased production of proinflammatory cytokines and the activation of STAT1. As Timmer and Nizet discuss, although therapeutically inhibiting IKKβ activity could be of benefit in the fight against tumors, doing so in the context of bacterial infection would be potentially more complicated.

T. Hagemann, T. Lawrence, I. McNeish, K. A. Charles, H. Kulbe, R. G. Thompson, S. C. Robinson, F. R. Balkwill, "Re-educating" tumor-associated macrophages by targeting NF-B. J. Exp. Med. 205, 1261-1268 (2008). [Abstract] [Full Text]

C. H. Y. Fong, M. Bebien, A. Didierlaurent, R. Nebauer, T. Hussell, D. Broide, M. Karin, T. Lawrence, An antiinflammatory role for IKKβ through the inhibition of "classical" macrophage activation. J. Exp. Med. 205, 1269-1276 (2008). [Abstract] [Full Text]

A. M. Timmer, V. Nizet, IKKβ/NF-B and the miscreant macrophage. J. Exp. Med. 205, 1255-1259 (2008). [Abstract] [Full Text]

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